Abstract
The effect of vertebral osteoporosis on disc degeneration is still debated. The purpose of this study was to provide a systematic review of studies in this area to further reveal the relationship between the two. Relevant studies were searched in electronic databases, and studies were screened according to inclusion and exclusion criteria, and finally, basic information of the included studies was extracted and summarized. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A total of 34 publications spanning 24 years were included in our study. There were 19 clinical studies, including 12 prospective studies and 7 retrospective studies. Of these, 7 considered vertebral osteoporosis to be positively correlated with disc degeneration, 8 considered them to be negatively correlated, and 4 considered them to be uncorrelated. Two cadaveric studies were included, one considered the two to be negatively correlated and one considered them not to be correlated. Seven animal studies were included, of which five considered a positive correlation between vertebral osteoporosis and disc degeneration and two considered a negative correlation between the two. There were also 6 studies that used anti-osteoporosis drugs for intervention, all of them were animal studies. Five of them concluded that vertebral osteoporosis was positively associated with disc degeneration, and the remaining one concluded that there was no correlation between the two. Our systematic review shows that the majority of studies currently consider an association between vertebral osteoporosis and disc degeneration, but there is still a huge disagreement whether this association is positive or negative. Differences in observation time and follow-up time may be one of the reasons for the disagreement. A large number of clinical and basic studies are still needed in the future to further explore the relationship between the two.
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Introduction
Intervertebral disc degeneration is a pathological change that occurs when the lumbar disc is damaged or ages with age. It can be induced by a variety of factors, such as mechanical loading, genetics, obesity, smoking, and aging. Although the mechanism remains unclear, degeneration and death of disc cells due to reduced nutrient supply, imbalance in microenvironmental homeostasis, infiltration of inflammatory factors, and altered mechanical loading are its main causes [4,5,6]. Another view is the exact opposite, that is, that a less dense vertebral body accelerates disc degeneration, while a healthy vertebral bone structure protects the disc [7,8,9]. Still others believe that the bone density of the vertebral body does not correlate with disc degeneration [10, 11].
A recent study based on quantitative Dixon and GRAPPATINI T2 map** techniques [4] found that disc degeneration caused by mechanical stress or aging often first manifests as loss of annulus fibrosus integrity, whereas the effect of osteoporosis on the lumbar disc is concentrated in the nucleus pulposus rather than the annulus fibrosus, suggesting that osteoporosis may directly trigger nucleus pulposus degeneration through the longitudinal structures (vertebral body-osseous endplates-bone marrow contact channels—cartilage endplates—nucleus pulposus), a pathological process completely different from disc degeneration caused by mechanical stress or aging.
Therefore, we believe that starting from the alteration of vertebral bone structure may provide a deeper understanding of the mechanisms of disc degeneration and may even lead to a potential means of intervention in the future. Over the last 20 years, there have been numerous clinical and animal studies to investigate the correlation between vertebral osteoporosis and disc degeneration. Unfortunately, no one has yet performed a systematic review of these studies. We believe that a systematic summary and evaluation of these studies is necessary. On the one hand, it helps one to understand the current research status in the field, and on the other hand, it helps to identify some shortcomings in the current research, which can provide guidance for future research design. Moreover, we may be able to find some common patterns from the existing research results, which can help to provide new ideas and entry points for future research.
Methods
This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [12].
Literature search strategy and selection criteria
We conducted a literature search using the following search terms: osteoporosis, bone density, intervertebral disc degeneration, and their combined forms in several electronic databases, PubMed(1966 to January 1, 2023), Cochrane Library (1966 to January 1, 2023), and Embase (1980 to January 1, 2023). Target articles were identified step by step based on title, abstract, and full text.
Ultimately, studies that met the following criteria were included: (1) studies exploring the relationship between vertebral osteoporosis or reduced bone density and intervertebral discs or endplates, including clinical studies and animal studies, with no restriction on the level of evidence, country and language; (2) clinical studies could be prospective or retrospective. There was no restriction on the duration of observation and the imaging means used; (3) there was also no restriction on the type of animals, strain, modelling method, intervention method, or observation time. Reviews, commentaries, letters to the editor, unpublished articles, and retracted articles were excluded. For studies that met the inclusion criteria, we also traced their references to identify potential studies. Also, some high-quality reviews were important references and basis for this study. The literature search and screening was conducted independently by two researchers. Any disagreements that arose during that process were resolved through discussion.
Data extraction
According to the purpose of our study, we extracted the following information from the included studies: first author, year of publication, type of study, imaging method and indicator, type of animal, modeling method, intervention method, observation time, results, and conclusions. This work was done independently by two researchers.
Quality assessment of the literature
We evaluated the quality of the included retrospective and prospective clinical studies using the Newcastle–Ottawa Scale (NOS) and the quality of the included animal studies using the initial Stroke Therapy Academic Industry Roundtable list (STAIR).
Results
Literature search results
According to the search strategy, we obtained a total of 114 relevant studies, and 83 after removing duplicates. After screening by title and abstract, a total of 35 papers were excluded. The remaining 48 studies were evaluated in full text, 14 of which were excluded because they did not meet the inclusion criteria, and 34 studies were finally included. The literature screening process is shown in Fig. 1. Basic information on the included clinical studies is shown in Table 1, basic information on the included animal studies is shown in Table 2, and basic information on the included drug therapy-related studies is shown in Table 3. Of the 34 studies, 17 considered positive correlation between vertebral osteoporosis and disc degeneration, 11 considered negative correlation, and 6 considered no correlation.
Clinical and cadaveric studies
We included a total of 21 clinical and cadaveric studies, including 12 prospective studies, 7 retrospective studies, and 2 cadaveric studies. Among the clinical studies, 7 studies considered vertebral osteoporosis to be positively associated with disc degeneration, 8 studies considered them to be negatively associated, and 4 studies considered them not to be associated. Of the cadaveric studies, 1 concluded that they were negatively correlated and 1 concluded that they were not correlated. The earliest of these studies was published in 1998 [21] and the most recent in 2022 [7]. The largest sample size was the study by Livshits et al. [16] and the smallest sample size was the study by Tosun et al. [6]. The middle-aged and older groups of men and women were the main subjects of clinical studies. In terms of imaging tools, the most used tool for measuring bone mineral density was dual-energy X-ray absorptiometry (DEXA), while some studies also used quantitative computed tomography (QCT). One study [14] used the dynamic computed tomographic perfusion (CTP) technique to detect indicators related to bone marrow microcirculation perfusion, and two other studies [7, 9] used Hounsfield Unit (HU) values from computed tomography (CT) instead of bone density. Magnetic resonance imaging (MRI) is a widely used tool to assess disc degeneration. Its indices are more diverse and include Pfirrmann grading (the most used), intervertebral space height, degree of endplate damage, bone redundancy formation, disc volume, and disc bulge rate. Two cadaveric studies [22, 25] used discography to assess the degree of disc degeneration and Micro-CT to measure bone density and endplate related parameters. With regard to the timing of assessment, most studies performed only one assessment of bone density and disc at sample entry, and only Salo et al. [23] performed three follow-up visits 5, 10, and 15 years after entry.
Animal studies
We included a total of 7 animal studies, of which 5 concluded that vertebral osteoporosis was positively associated with disc degeneration and 2 concluded that they were negatively associated. The earliest of these animal studies was published in 2004 [32] and the most recent study [30] combined paravertebral muscle dissection with ovariectomy. In terms of observation time, Zhang et al. [4, 5, and 6.
CT computed tomography, HU Hounsfield Unit, MRI magnetic resonance imaging, TEPS total endplate score, DEXA dual-energy X-ray absorptiometry, BMD bone mineral density, CTP dynamic computed tomographic perfusion, Ha anterior height, Hm middle height, Hp posterior height, AP anteriorposterior dimension, MZ monozygotic, DZ dizygotic, LDD lumbar disc degeneration, QCT quantitative computed tomography, Q-Dixon quantitative Dixon, Int.BMD integral BMD, Tb.BMD trabecular BMD, Trab.vBMD trabecular volumetric BMD, M male, F female, BMC bone mineral content, BV bone volume, TV total volume, BV/TV percentage bone volume, BS bone surface density, Tb.N trabecular number, Tb.Th trabecular thickness, Tb.Sp trabecular separation, SMI structural model index, BMDtv total volume of bone mineral density, Tb.Pf trabecular pattern factor, CONN.D connectivity density, Po.N(cl) number of closed pores, PO(op) open porosity, Po.V(tot) total volume of pore space, Mdtv mean density of TV, DHI disc height index, IDH intervertebral disc height, VEL vertebral endplates lesions, SD Sprague Dawley, OVX ovariectomy, Opg osteoprotegerin, KO knockout, VEGF-A vascular endothelial growth factor-A, IL-1β interleukin-1β, TNF-α tumor necrosis factor-α, PYM **yangmycin, CMS cervical muscle section.
Discussion
The physiological and pathological characteristics of intervertebral discs, such as their anatomical structure, nutritional pathways, and mechanical properties, have been studied quite thoroughly as early as the last century. In recent years, although clinical and basic research on discs is still gradually increasing, there seems to be few groundbreaking findings. For disc degeneration, there is also still no recognized effective intervention and remains one of the most urgent challenges to be solved. When it comes to vertebral osteoporosis, more attention is often paid to the vertebral fractures caused by it and its impact on lumbar spine surgery, such as on the stability of intervertebral fusion devices and pedicle screws. There are not many studies examining the effects of vertebral osteoporosis on disc degeneration, and the findings are divergent. Therefore, we designed this study. To our knowledge, this is the first time in the last two decades that a systematic and comprehensive review and summary of relevant studies has been performed. This helps one to understand the points of controversy and the problems with the current study, so that the next studies can be improved in a targeted manner.
In this systematic review, we have made a comprehensive and detailed summary and presentation of the basic information of 34 studies, such as study type, sample information, imaging methods, modeling methods, observation time, results, and conclusions, and we have also evaluated the quality of these studies. Of the 34 studies, 17 concluded that vertebral osteoporosis was positively correlated with disc degeneration, 11 concluded that they were negatively correlated, and 6 concluded that they were not correlated. Most of the retrospective clinical studies we included were cross-sectional studies, which had a high risk of bias and a limited level of evidence. Prospective studies were more convincing than retrospective studies, but these studies lacked long follow-up. Moreover, the included clinical studies commonly used DEXA to measure BMD, and their results are susceptible to interference from other tissues [20]. In addition, these clinical studies could not be explored in greater depth at the level of mechanism of action. The animal studies we included were small in number and each had a small sample size, but they provided a wealth of histological evidence in addition to imaging findings. Moreover, these animal studies commonly used Micro-CT to measure bone trabecular structures as well as endplate microstructure, which is more accurate than DEXA. Encouragingly, several studies [61] concluded that the rate of glucose diffusion into the disc significantly decreases as the static compressive strain of the disc increases. When the vertebral bone density decreases, the endplate resistance decreases and the compressive strain of the disc decreases, which facilitates the diffusion of glucose and delays the degeneration of the disc.
Contrary to the above, other evidence suggests that the vertebral body after osteoporosis does not act as a stress buffer, but rather increases the mechanical stresses on the endplate and disc. Finite element models [73] showed that when the modulus of trabeculae decreased by 50%, the peak stress on the endplate increased by 74%, eventually leading to endplate thinning, calcification [74], and even collapse [25, 75, 76]. Histological evidence also suggests the presence of many active small chondrocytes within the cartilage endplate adjacent to the nucleus pulposus, which is considered an indication of abnormal endplate loading [77]. The overgrowth of bony flaps at the edges of the vertebral body in osteoporotic rats is also an evidence of increased disc stress [78]. We believe that the force patterns of the lumbar spine are different in humans and experimental animals. Humans walk upright, whereas experimental animals are crawlers. Therefore, clinical studies may reach different conclusions than animal studies, which may be one of the reasons for the disagreement. In addition, the difference in observation time between the above studies may also contribute to the disagreement. Bone loss is a long-term process. In the early stages, a mild decrease in vertebral bone density may serve to cushion the pressure to protect the disc, but this cushioning effect may be difficult to maintain as the bone structure gradually deteriorates. Unfortunately, no one has yet observed the dynamic effects of vertebral bone density on the disc at different times. Therefore, this question still needs to be answered by more future studies.
Disc height
Changes in disc height after reduction in vertebral bone density were observed in several animal experiments and clinical studies in our included studies [6, 15, 17, 24]. Exceptionally, disc height changes under osteoporosis are more often reflected in an increase in the intermediate disc height [6, 24], whereas the anterior and posterior disc heights do not seem to change significantly [24]. Biomechanical studies have shown that osteoporosis leads to a concentration of stress in the center of the vertebral endplate, and the increased pressure leads to trabecular compression and axial bulging of the endplate [79]. This is therefore manifested on imaging as an increased concavity of the endplate [24], leading to an increase in the intermediate height of the disc. However, it is important to point out that this is a secondary change due to the additional expansion space created by the increased concavity of the endplate and the compression of the vertebral body, and is not a change in the state of the disc itself. It is also believed a loss of vertebral body height due to osteoporosis causes instability of the spinal motion segment and accelerates degeneration of the articular eminence joint and disc [17, 80]. We suggest that when exploring disc height, humans and animals similarly show different results depending on different walking patterns. Changes in disc height may be more pronounced in humans who walk upright relative to animals who crawl. Therefore, the plausibility of using animal disc height changes to model human disc degeneration seems to be debatable.
Imaging tools
DEXA is the most widely used method for screening and diagnosis of osteoporosis. It has the advantage of being technically mature, easy to perform, and inexpensive, but it has limitations in terms of spatial resolution and is susceptible to interference from endplate sclerosis, bone redundancy, and ligamentous calcification, leading to falsely elevated measurements [20]. Therefore, it has been suggested [23, 26] that the conclusion that higher BMD is associated with more severe disc degeneration may be related to the falsely elevated BMD values caused by DEXA. Furthermore, DEXA does not allow for the quantitative analysis of bone tissue in the target region. In view of this limitation, more and more studies have started to use Q-CT and Micro-CT to quantify the microstructure of bone trabeculae in the target region after differentiating between cortical and cancellous bone to reduce the interference of other structures. Micro-CT can clearly scan bone trabeculae in the target area at the micron level, calculate bone structural parameters precisely and in three dimensions, and detect early changes in bone microstructure. Some impressive studies [25, 29] used Micro-CT to precisely delineate the target area, segment the endplate, and directly measure the calcified area, thickness, and porosity of the endplate to observe structural changes in the endplate from a more microscopic perspective. However, Micro-CT is not as popular as DEXA due to its high price, complicated operation, and high radiation dose, and is currently used more for basic research. There is also an alternative method of assessing BMD using the HU value, which is based on the existence of a strong positive correlation between HU values and BMD [9]. As an alternative method, no additional examination costs are required and the procedure is relatively simple. In the previously mentioned section on bone marrow perfusion, functional CTP imaging has been used to quantify the spatio-temporal distribution patterns of bone marrow microcirculation perfusion and bone density, which is also an emerging technical tool for the assessment of hemodynamics by continuous measurement of multiplanar imaging [14]. As for the assessment of disc degeneration, it is evident from the included studies that MRI is still the most commonly used imaging method to assess the disc.
Animal models of osteoporosis
Cost is an important factor influencing the choice of experimental animals. In our included studies, rats and mice remained the most used animals due to their lower cost. Primates share anatomical, physiological and biomechanical similarities with humans and are higher up in the phylogenetic tree. Of the studies we included, only one study [29] used rhesus monkeys for the study. We believe that large-scale use of primates may remain elusive due to high costs. Accelerated bone turnover due to estrogen deficiency is the most common cause of osteoporosis. Therefore, the animal model of osteoporosis caused by estrogen deficiency is the most used animal model in our included studies. This model was constructed by bilateral oophorectomy, which is a mature technique, simple to perform, and has a high modeling rate. Other studies have used models of natural aging, which have a longer experimental period and higher time cost. OPG exerts an inhibitory effect on the differentiation, activation and survival of osteoblasts. One study [28] used a mouse model with OPG knockout, again limited by cost and difficult to apply on a large scale. Other studies have used composite models, which add to the OVX model by removing paravertebral muscles to exacerbate lumbar instability [30] or by injecting drugs into the endplate to block the nutrient supply to the disc [29], achieving a more significant disc degeneration effect than the OVX model alone and shortening the experimental period.
Limitations
We have the following limitations in this study. First, the included studies were highly variable with few common outcome indicators, so we were unable to perform a quantitative meta-analysis of the valuable outcome indicators to increase the persuasiveness. Second, because disc degeneration is the result of a combination of factors and there is no ideal experimental model to date that can model any one of these factors alone [14]. Therefore, the studies we included only illustrate the correlation between vertebral osteoporosis and disc degeneration without revealing a causal relationship between the two. In addition, the relationship between vertebral osteoporosis and disc degeneration may not be one-sided, but rather an interactive relationship. Disc degeneration can likewise have an impact on vertebral bone density. Some studies [6, 10, 23] have shown that when the disc degenerates, the load shifts from the nucleus pulposus to the annulus fibrosus and the stress on the vertebral wall and posterior structures increases, leading to a decrease in core bone density and an increase in bone density in the vertebral wall and posterior structures. However, due to space limitations, we did not explore the effect of disc degeneration on vertebral bone density. Finally, osteoporosis is a systemic disease, and more in-depth studies on the relationship between vertebral and extremity bone density, as well as the relationship between disc degeneration and extremity bone density, are still pending [16, 18, 81, 82], which is our next step to focus on.
Conclusion
Our systematic review shows that the majority of studies currently consider an association between vertebral osteoporosis and intervertebral disc degeneration, but there is still a huge disagreement whether this association is positive or negative. Differences in observation time and follow-up time may be one of the reasons for the disagreement. Our view is that vertebral osteoporosis may have a bidirectional effect on disc degeneration. At different stages in the progression of osteoporosis, the effect on disc degeneration shows different trends. Therefore, for future clinical and animal studies, we not only recommend the use of more precise imaging tools such as QCT and Micro-CT, but also the setting of different observation time points to explore the dynamic relationship between vertebral osteoporosis and disc degeneration.
Data availability
All data generated or analyzed during this study are included in this article.
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Li, W., Zhao, H., Zhou, S. et al. Does vertebral osteoporosis delay or accelerate lumbar disc degeneration? A systematic review. Osteoporos Int 34, 1983–2002 (2023). https://doi.org/10.1007/s00198-023-06880-x
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DOI: https://doi.org/10.1007/s00198-023-06880-x