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Quantitative histologic data on disuse osteoporosis
Abstract
The effect of immobilization on human bone was studied through a longitudinal, as well as cross-sectional, quantitative and
dynamic histological analysis of 34 decalcified and undecalcified iliac crest biopsies. They were obtained at various times
after the onset of immobilization in 28 patients of which 22 were suffering from post-traumatic spinal cord lesions. Trabecular
bone volume, osteoid volume, trabecular osteoclastic resorption surfaces, size of the periosteocytic lacunae, thickness of
iliac cortices and volume of the cell population of the marrow were measured. The histodynamic study was made by double tetracycline
labeling in 19 patients. The histological data were compared with biological data from another group of 68 immobilized patients
including 22 of the patients undergoing biopsy. Calcemia, phosphoremia, alkaline phosphatase, calciura, phosphaturia and hydroxyprolinuria
were measured. The decrease of the trabecular bone volume averaged 33% over 25 weeks and then stabilized. Immobilization also
caused an early increase in the trabecular osteoclastic resorption surfaces and later in the size of periosteocytic lacunae,
an early depression of osteoblastic bone formation and a thinning of the cortices. Calciuria was high, as was hydroxyprolinuria
which correlates with resorption surfaces. The histological and biochemical changes suggest an histodynamic hypothesis according
to which the global lifespan of the BMU (Basic Multicellular Unit from Frost) would be increased. These changes reflect atransient, leading to a newsteady state: rarefied bone with a low rate of subsequent turn-over. They emphasize the importance of mechanical factors in the development
of bone cells.
... This can be best illustrated through osteopenia and osteoporosis, which are bone metabolic conditions characterized by increased bone fragility. While their etiology is complex, it also includes lack of biomechanical stimulation, as bone remodeling is disrupted for prolonged periods of time, such as in cases of bedrest or immobilization (e.g., Minaire et al. 1974;Schlecht et al. 2012). Infectious bacterial diseases, such as tuberculosis, which result in bone lesions including tuberculosis-induced hypertrophic osteopathy (Von Hunnius 2009) or local deposition of woven bone in response to the infection (Kuhn et al. 2007), can be examined alongside bone remodeling changes (Nair et al. 1996). ...
... The knowledge of modern-day presentation of remodeling changes in biomechanical and pathological contexts, combined with histology, offers a powerful means with which to test the extent that localized, cortical-bone mechanical adaptation occurs in archaeological cases of limb immobilization and disuse (e.g., Minaire et al. 1974;Schlecht et al. 2012). This histological approach may also enhance interpretations in bioarchaeology by identifying whether bone remodeling changes occurred as a result of long-or short-term disuse (Miszkiewicz et al. 2020). ...
Bone is dynamic, undergoing metabolic changes in response to behavioral and pathological stimuli. This information can be reconstructed in bioarchaeology using histological methods, providing another avenue to explore the experiences of past peoples. We report histological findings from midshaft femoral cortical bone of an identified individual from nineteenth-century New Zealand, who suffered from tuberculosis and had a historically documented period of invalidism. Materials: Burial 21 (B21) is a middle-aged male excavated from the nineteenth-century site of St. John’s burial ground, Milton. B21’s left proximal femur and acetabulum exhibited lytic lesions associated with tuberculosis-induced destruction of bone. Documentation, including a cause of death of “pneumonic phthisis haemorrhage,” and various biographic details exist for this burial. These suggest that B21’s left and right midshaft femur were under asymmetric biomechanical and pathological conditions and should show differences in the underlying bone remodeling. Methods: We collected data on Haversian bone microstructure geometric properties and densities from a total of 148 secondary osteons and 481 Haversian canals. Results: The left femur, from the tuberculosis-inflicted hip joint, had fewer, larger, and more irregularly shaped canals and osteons than the right femur. Discussion and Conclusion: These findings may indicate the left femur received less biomechanical stimulation than the right femur due to decreased weightbearing. It is also possible that the tuberculosis infection in this individual impacted his bone metabolic activity, leading to increased experiences of bone loss. The presented histological approach may enhance interpretations in bioarchaeology by identifying whether bone remodeling changes occur as a result of long-or short-term disuse.
... This accumulation of bone marrow fat shows a strong association with bone loss, reduced bone formation, and fracture risk (6)(7)(8)(9). Mesenchymal progenitors (MSCs) within bone marrow can be directed toward the AC or osteoblast lineage, and conditions that favor adipogenesis such as estrogen depletion (10), disuse (11), anorexia/calorie restriction (12,13), and exposure to microgravity (14) are also associated with reduced osteoblast differentiation. ...
... Unloading through either prolonged bedrest or spaceflight increases bone marrow adipogenesis (11,14), and prolonged bedrest also decreases muscle strength and increases IMC lipid in skeletal muscle (50), which can ultimately lead to postural instability (51). Finally, estrogen deficiency is implicated in bone loss and marrow AC accumulation in women. ...
Skeletal muscle and bone share common embryological origins from mesodermal cell populations and also display common growth trajectories early in life. Moreover, muscle and bone are both mechanoresponsive tissues, and the mass and strength of both tissues decline with age. The decline in muscle and bone strength that occurs with aging is accompanied in both cases by an accumulation of adipose tissue. In bone, adipocyte (AC) accumulation occurs in the marrow cavities of long bones and is known to increase with estrogen deficiency, mechanical unloading, and exposure to glucocorticoids. The factors leading to accumulation of intra- and intermuscular fat (myosteatosis) are less well understood, but recent evidence indicates that increases in intramuscular fat are associated with disuse, altered leptin signaling, sex steroid deficiency, and glucocorticoid treatment, factors that are also implicated in bone marrow adipogenesis. Importantly, accumulation of ACs in skeletal muscle and accumulation of intramyocellular lipid are linked to loss of muscle strength, reduced insulin sensitivity, and increased mortality among the elderly. Resistance exercise and whole body vibration can prevent fatty infiltration in skeletal muscle and also improve muscle strength. Therapeutic strategies to prevent myosteatosis may improve muscle function and reduce fall risk in the elderly, potentially impacting the incidence of bone fracture.
... Bone tissue associated with limb under-use or disuse experiences accelerated deterioration as osteoclast-mediated bone resorption predominates bone formation by osteoblasts (Alexandre and Vico, 2011). Indeed, "disuse osteoporosis" is used to describe negative effects of bed-rest or weightlessness that ultimately lead to bone loss and reduced strength (Minaire et al., 1974;Alexandre and Vico, 2011;Bartl and Bartl, 2017). Classic bone functional adaptation predictions, based on models outlined in the Utah Paradigm of Skeletal Physiology (Frost, 1987(Frost, , 20002003), project that abnormally low levels of mechanical strain increase bone disuse remodeling through prolonged osteoclast activity (Robling et al., 2006) (see Supplement 1). ...
Objective
This study investigated microstructural changes of the right and left midshaft femur in an archaeological individual afflicted with left-sided hip joint ankylosis to assess whether increased cortical porosity was present as a result of leg disuse.
Materials
The individual is a middle-aged adult male excavated from the Metal Period (∼2000 BP) Nagsabaran, Luzon Island, Philippines.
Methods
Following standard examination of femur gross anatomy and differential diagnosis of the hip joint fusion, ∼1 cm thick posterior midshaft femur samples were removed for microstructural examination. Using static histomorphometry, bone multi-cellular unit activity from Haversian canal (vascular pore) density, area, and circularity was reconstructed. Spatial positioning of Haversian canals was mapped using Geographic Information Systems software. Phosphate, carbonate, and carbonate:phosphate ratios were obtained using synchrotron-sourced Fourier transform infrared microspectroscopy.
Results
The left femur had greater cortical pore density, with smaller and rounder vascular canals, in addition to lower matrix levels of phosphate and carbonate, when compared to the right femur.
Conclusions
Our data indicate compromised bone tissue in the left femur, and conform to expected bone functional adaptation paradigms of remodeling responses to pathological and biomechanical changes.
Significance
The preservation of this individual’s hip abnormality created a unique opportunity to evaluate intra-skeletal bone health asymmetry, which may help other researchers evaluate the presence of limb disuse in archaeological samples.
Limitations
A lack of lower limb data limits our interpretations to femur remodeling only.
Suggestions for Further Research
Future research efforts should aim to examine the presence of remodeling changes in all bones of the lower limb.
Layunin
Gamit ang buto ng magkabilang pemur ng isang taong natagpuan sa isang archaeological site na may sakit na ankylosis sa kaliwang balakang, pinag-aralan ang iba’t-ibang microstructures galing sa gitnang bahagi o midshaft ng pemur upang malaman kung may makikitang mataas na cortical porosity ang buto dahil hindi ito malimit gamitin.
Gamit
Ang pinag-aaralang buto ay galing sa isang indibidwal na tinatayang middle-age na lalaki na namuhay noong Panahon ng Metal (∼2000 BP) sa Nagsabaran, Cagayan, Republika ng Pilipinas.
Pamamaraan
Matapos ang unang pagkilatis sa femur at ang pagkilala ng sakit sa balakang, kumuha ng ∼1 sentimetro ng buto galing sa midshaft ng pemur upang lalong mapag-aralan ang kanyang microstructure. Gamit ang static histomorphometry, napag-aralan ang mga naiwang bakas ng multi-cellular unit activity ayon sa kapal, laki at pagkakabilog ng Haversian canal (vascular pore). Gumamit din ng Geographic Information Systems (GIS) software upang mapag-aralan ang kaugnayan ng posisyon ng Haversian canal. Panghuli, gumamit din ng synchroton-sourced Fourier transform infrared (sFTIR) microspectroscopy upang makuha ang bilang ng phosphate, carbonate, at carbonate:phosphate ratio.
Resulta
Napag-alaman na ang kaliwang pemur ay mayroong higit na maraming cortical pores, maliit at mabilog na vascular canals, at mababang bilang ng phosphate, carbonate kung ihahambing sa kanang pemur.
Konklusyon
Ayon sa aming datos, ang kaliwang pemur ay umaayon sa mga katangian ng isang butong may sakit. Sumunod din ito sa inaasahang bone functional adaptation paradigms of remodeling ng buto dahil may sakit at hindi nagamit.
Kahalagahan
Dahil maganda ang pagkakalibing ng buto ng balakang, nagkaroon ng pagkakataong makilatis ang kalusugan ng sinaunang-tao sa pamamagitan ng pag-aaral ng kalusugan ng buto. Dagdag pa, makakatulong din ito upang malaman kung ibang mananaliksik ang pag-aaral ng ibang butong hindi nagagamit mula sa archaeological site.
Limitasyon
Dahil walang nakuhang ibang buto mula sa binti at paa, ang pemur lang ang naimbestigahan.
Mungkahi para sa mga susunod na pag-aaral
Kung magkakaroon ng pagkakataon sa susunod, dapat maimbistigahan ang lahat ng buto ng binti (lower limb).
Rapid and extensive sublesional bone loss after spinal cord injury (SCI) is a difficult medical problem that has been refractory to available interventions except the antiresorptive agent denosumab (DMAB). While DMAB has shown some efficacy in inhibiting bone loss, its concurrent inhibition of bone formation limits its use. Sialic acid‐binding immunoglobulin‐like lectin (Siglec)‐15 is expressed on the cell surface of mature osteoclasts. Anti‐Siglec‐15 antibody (Ab) has been shown to inhibit osteoclast maturation and bone resorption while maintaining osteoblast activity, which is distinct from current antiresorptive agents that inhibit the activity of both osteoclasts and osteoblasts. The goal of the present study is to test a Siglec‐15 Ab (NP159) as a new treatment option to prevent bone loss in an acute SCI model. To this end, 4‐month‐old male Wistar rats underwent complete spinal cord transection and were treated with either vehicle or NP159 at 20 mg/kg once every 2 weeks for 8 weeks. SCI results in significant decreases in bone mineral density (BMD, −18.7%), trabecular bone volume (−43.1%), trabecular connectivity (−59.7%), and bone stiffness (−76.3%) at the distal femur. Treatment with NP159 almost completely prevents the aforementioned deterioration of bone after SCI. Blood and histomorphometric analyses revealed that NP159 is able to greatly inhibit bone resorption while maintaining bone formation after acute SCI. In ex vivo cultures of bone marrow cells, NP159 reduces osteoclastogenesis while increasing osteoblastogenesis. In summary, treatment with NP159 almost fully prevents sublesional loss of BMD and metaphysis trabecular bone volume and preserves bone strength in a rat model of acute SCI. Because of its unique ability to reduce osteoclastogenesis and bone resorption while promoting osteoblastogenesis to maintain bone formation, Siglec‐15 Ab may hold greater promise as a therapeutic agent, compared with the exclusively antiresorptive or anabolic agents that are currently used, in mitigating the striking bone loss that occurs after SCI or other conditions associated with severe immobilization. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
Background:
The prevention of lower extremity fractures and fracture-related morbidity and mortality is a critical component of health services for adults living with chronic spinal cord injury (SCI).
Methods:
Established best practices and guideline recommendations are articulated in recent international consensus documents from the International Society of Clinical Densitometry, the Paralyzed Veterans of America Consortium for Spinal Cord Medicine and the Orthopedic Trauma Association.
Results:
This review is a synthesis of the aforementioned consensus documents, which highlight the pathophysiology of lower extremity bone mineral density (BMD) decline after acute SCI. The role and actions treating clinicians should take to screen, diagnose and initiate the appropriate treatment of established low bone mass/osteoporosis of the hip, distal femur or proximal tibia regions associated with moderate or high fracture risk or diagnose and manage a lower extremity fracture among adults with chronic SCI are articulated. Guidance regarding the prescription of dietary calcium, vitamin D supplements, rehabilitation interventions (passive standing, functional electrical stimulation (FES) or neuromuscular electrical stimulation (NMES)) to modify bone mass and/or anti-resorptive drug therapy (Alendronate, Denosumab, or Zoledronic Acid) is provided. In the event of lower extremity fracture, the need for timely orthopedic consultation for fracture diagnosis and interprofessional care following definitive fracture management to prevent health complications (venous thromboembolism, pressure injury, and autonomic dysreflexia) and rehabilitation interventions to return the individual to his/her pre-fracture functional abilities is emphasized.
Conclusions:
Interprofessional care teams should use recent consensus publications to drive sustained practice change to mitigate fracture incidence and fracture-related morbidity and mortality among adults with chronic SCI.
Changes in bone architecture and metabolism with aging increase the likelihood of osteoporosis and fracture. Age-onset osteoporosis is multifactorial, with contributory extrinsic and intrinsic factors including certain medical problems, specific prescription drugs, estrogen loss, secondary hyperparathyroidism, microenvironmental and cellular alterations in bone tissue, and mechanical unloading or immobilization. At the histological level, there are changes in trabecular and cortical bone as well as marrow cellularity, lineage switching of mesenchymal stem cells to an adipogenic fate, inadequate transduction of signals during skeletal loading, and predisposition toward senescent cell accumulation with production of a senescence-associated secretory phenotype. Cumulatively, these changes result in bone remodeling abnormalities that over time cause net bone loss typically seen in older adults. Age-related osteoporosis is a geriatric syndrome due to the multiple etiologies that converge upon the skeleton to produce the ultimate phenotypic changes that manifest as bone fragility. Bone tissue is dynamic but with tendencies toward poor osteoblastic bone formation and relative osteoclastic bone resorption with aging. Interactions with other aging physiologic systems, such as muscle, may also confer detrimental effects on the aging skeleton. Conversely, individuals who maintain their BMD experience a lower risk of fractures, disability, and mortality, suggesting that this phenotype may be a marker of successful aging. © 2023 American Physiological Society. Compr Physiol 13:4355-4386, 2023.
Spinal cord injury (SCI) results in significant loss of sublesional bone, adding to the comorbidity of SCI with an increased risk of fracture and post-fracture complications. Unfortunately, the effect of SCI on skeletal health is also likely to rise as the average age of SCI has increased and there are well-known negative effects of age on bone. To date, however, the impact of age and age-associated inflammation (inflammaging) on skeletal health after SCI remains largely unknown. To address this, we compared bone parameters in young (3 month) and middle-aged (9 month) male and female rats with a moderate thoracic contusion injury, to age and sex matched sham-operated controls. Skeletal parameters, locomotor function and serum cytokine levels were assessed at both subchronic (30 days) and chronic (180 days) time points post injury. We hypothesized that SCI would lead to a dramatic loss of bone immediately after injury in all SCI-groups, with inflammaging leading to greater loss in middle-aged SCI rats. We also predicted that while younger rats may re-establish bone properties in more chronic phases of SCI, middle-aged rats would not. Supporting these hypothesis, trabecular bone volume was significantly lower in male and young female SCI rats early after injury. Contrary to our hypothesis, however, there was greater loss of trabecular bone volume, relative to age-matched shams, in young compared to middle-aged SCI rats with no effects of SCI on trabecular bone volume in middle-aged female rats. Moreover, despite recovery of weight-supported locomotor activity, bone loss persisted into the chronic phase of injury for the young rats. Bone formation rates were lower in young male SCI rats, regardless of the time since injury, while both young and middle-aged female SCI rats had lower bone formation in the subchronic but not chronic phase of SCI. In middle-aged rats, SCI-induced higher osteoclast surfaces, which also persisted into the chronic phase of SCI in middle-aged females. Neither age nor SCI-induced increases in inflammation seemed to be associated with bone loss. In fact, SCI had more dramatic and persistent effects on bone in male rats, while aging and SCI elevated serum cytokines only in female rats. Overall, this study demonstrates SCI-induced loss of bone and altered bone turnover in male and female rats that persists into the chronic phase post-injury. The sex and age dependent variations in bone turnover and serum cytokines, however, underscore the need to further explore both mechanisms and potential therapeutics in multiple demographics.
Objectives
Persons with traumatic spinal cord injury (SCI) have severe bone loss below the level of lesion with the distal femur (DF) and proximal tibia (PT) being the skeletal regions appreciated to have the highest risk of fracture. While a reference areal bone mineral density (aBMD) database is available at the total hip (TH) using the combined National Health and Nutrition Examination Survey (NHANES) III study and General Electric (GE) combined (GE/NHANES) to calculate T-score (T-scoreGE/NHANES), no such reference database exists for aBMD of the DF and PT. The primary objectives of this study were (1) to create a reference dataset of young-healthy able-bodied (YHAB) persons to calculate T-score (T-scoreYHAB) values at the DF and PT, (2) to explore the impact of time since injury (TSI) on relative bone loss in the DF and PT regions using the two computation models to determine T-score values, and (3) to determine agreement between T-score values for a cohort of persons with SCI using the T-scoreYHAB and T-scoreGE/NHANES reference datasets.
Design
A cross-sectional prospective data collection study.
Setting
A Department of Veterans Affairs Medical Center and a Private Rehabilitation Hospital.
Participants
A normative reference aBMD database at the DF and PT was collected in 32 male and 32 female Caucasian YHAB participants (n=64) and then applied to calculate T-score values at the DF and PT in 105 SCI participants from a historical cohort. The SCI participants were then grouped based on TSI epochs (E-I: TSI < 1y, E-II: TSI 1-5y, E-III: TSI 6-10y, E-IV: TSI 11-20y, E-V: TSI > 20y).
Interventions
N/A.
Main Outcome Measures
The knee and hip aBMD values were obtained by dual energy X-ray absorptiometry (GE Lunar iDXA) using standard clinical software for proximal femur orthopedic knee software applications.
Results
There were no significant differences in mean aBMD values across the four YHAB age subgroups (21-25, 26-30, 31-35, and 36-40 years of age) at the TH, DF, and PT, and mean aBMD values were higher in men compared to the women at all skeletal regions of interest. Using the mean YHAB aBMD values to calculate T-score values at each TSI epoch for persons with SCI, T-score values decreased as a function of TSI and continued to decline for 11-20 years. Moderate kappa agreement was noted between the YHAB and the GE/NHANES reference datasets for the T-score cutoff criteria accepted to diagnose osteoporosis (i.e., SD <-2.5).
Conclusions
A homogeneous reference dataset of YHAB aBMD values at the DF and PT was applied to calculate T-score values in persons with chronic SCI. There was a moderate level of agreement at the TH between the YHAB and GE/NHANES reference datasets when applying the conventional T-score cutoff value for the diagnosis of osteoporosis.
Spinal cord injury (SCI) produces paralysis and a unique form of neurogenic disuse osteoporosis that dramatically increases fracture risk at the distal femur and proximal tibia. This bone loss is driven by heightened bone resorption and near-absent bone formation during the acute post-SCI recovery phase and by a more traditional high-turnover osteopenia that emerges more chronically, which is likely influenced by the continual neural impairment and musculoskeletal unloading. These observations have stimulated interest in specialized exercise or activity-based physical therapy (ABPT) modalities (e.g., neuromuscular or functional electrical stimulation cycling, rowing, or resistance training, as well as other standing, walking, or partial weight-bearing interventions) that reload the paralyzed limbs and promote muscle recovery and use-dependent neuroplasticity. However, only sparse and relatively inconsistent evidence supports the ability of these physical rehabilitation regimens to influence bone metabolism or to increase bone mineral density (BMD) at the most fracture-prone sites in persons with severe SCI. This review discusses the pathophysiology and cellular/molecular mechanisms that influence bone loss after SCI, describes studies evaluating bone turnover and BMD responses to ABPTs during acute versus chronic SCI, identifies factors that may impact the bone responses to ABPT, and provides recommendations to optimize ABPTs for bone recovery.
The administration of high-dose methylprednisolone (MP) for 24–48 h after traumatic spinal cord injury (SCI) has been shown to improve functional recovery. The known adverse effects of MP on skeletal muscle and the immune system, though, have raised clinically relevant safety concerns. However, the effect of MP administration on SCI-induced bone loss has not been evaluated to date. This study examined the adverse effects of high-dose MP administration on skeletal bone after acute SCI in rodents. Male rats underwent spinal cord transection at T3–T4, which was followed by an intravenous injection of MP and subsequent infusion of MP for 24 h. At 2 days, animals were euthanized and hindlimb bone samples were collected. MP significantly reduced bone mineral density (−6.7%) and induced deterioration of bone microstructure (trabecular bone volume/tissue volume, −18.4%; trabecular number, −19.4%) in the distal femur of SCI rats. MP significantly increased expression in the hindlimb bones of osteoclastic genes receptor activator of nuclear factor-κB ligand (RANKL; +402%), triiodothyronine receptor auxiliary protein (+32%), calcitonin receptor (+41%), and reduced osteoprotegerin/RANKL ratio (−72%) compared to those of SCI-vehicle animals. Collectively, 1 day of high-dose MP at a dose comparable to the dosing regimen prescribed to patients who qualify to receive this treatment approach with acute SCI increased loss of bone mass and integrity below the level of lesion than that of animals that had SCI alone, and was associated with further elevation in the expression of genes involved in pathways associated with osteoclastic bone resorption than that observed in SCI animals.
Spinal cord injury (SCI) results in rapid, marked skeletal deterioration below the level of neurological lesion. Ideally, the most effective therapeutic approach would prevent loss of bone mass and architecture shortly after paralysis. Bisphosphonates preserve bone mineral density at the hip but not at the knee, which is the anatomical site most prone to fracture in the SCI population. Denosumab has recently been reported to prevent bone loss in persons with acute SCI but should be continued for an as yet indeterminate time because discontinuation will result in rapid bone loss. Several other novel approaches to preserving bone at the time of acute SCI should be tested, as well as approaches to reverse bone loss in individuals with chronic SCI.
Diminished bone perfusion develops in response to disuse and has been proposed as a mechanism underlying bone loss. Bone blood flow (BF) has not been investigated within the unique context of severe contusion spinal cord injury (SCI), a condition that produces neurogenic bone loss that is precipitated by disuse and other physiologic consequences of central nervous system injury. Herein, 4-mo-old male Sprague-Dawley rats received T9 laminectomy (SHAM) or laminectomy with severe contusion SCI (N=20/group). Time course assessments of hindlimb bone microstructure and bone perfusion were performed in vivo at 1- and 2-wks post-surgery via microCT and intracardiac microsphere infusion, respectively, and bone turnover indices were determined via histomorphometry. Both groups exhibited cancellous bone loss beginning in the initial post-surgical week, with cancellous and cortical bone deficits progressing only in SCI thereafter. Trabecular bone deterioration coincided with uncoupled bone turnover after SCI, as indicated by signs of ongoing osteoclast-mediated bone resorption and a near-complete absence of osteoblasts and cancellous bone formation. Bone BF was not different between groups at 1-wk, when both groups displayed bone loss. In comparison, femur and tibia perfusion was 30-40% lower in SCI vs SHAM at 2-wks, with the most pronounced regional BF deficits occurring at the distal femur. Significant associations existed between distal femur BF and cancellous and cortical bone loss indices. Our data provide the first direct evidence indicating bone BF deficits develop in response to SCI and temporally coincide with suppressed bone formation and with cancellous and cortical bone deterioration.
During the acute and chronic phase of spinal cord injury (SCI) bone turnover and structure are affected. Bone mineral density of lower limbs is decreased up to 28-50% below that of age-matched peers at 12–18 months post injury. Coexisting secondary etiologies of osteoporosis may be present, and during ageing additional loss of bone occurs. All these compose a complex canvas of bone impairment after spinal cord injury and make the therapeutical approach challenging. The risk of fragility fractures is increased after the 2nd decade post SCI affecting the functionality and quality of life of individuals with SCI.
Diagnostic flaws, lack of a ranking system to categorize the degree of bone impairment similar to the one of World Health Organization, and evidence-based clinical guidelines for management in SCI requires interdisciplinary cooperation and appropriate planning of future research and interventions.
Spinal Cord Section of Hellenic Society of Physical Rehabilitation Medicine (HeSCoSPRM) convened an expert panel working group on bone and spinal cord injury at the Pan-Hellenic Congress 2018 of PRM in Athens Greece, to establish an evidence-based position statement for bone loss in individuals with SCI of traumatic or non-traumatic etiology. This was reviewed by an International Task Force and used to create S1 Guidelines.
This first version S1 guideline will work towards to provide help with prophylactic basic osteoporosis therapy diagnostic and therapeutic decisions in acute and chronic phase and rehabilitation countermeasures against osteoporosis related with spinal cord injury.
Bromer, Frederik Duch, Mikkel Bo Brent, Michael Pedersen, Jesper Skovhus Thomsen, Annemarie Brüel, and Casper Bindzus Foldager. The effect of normobaric intermittent hypoxia therapy on bone in normal and disuse osteopenic mice. High Alt Med Biol. 00:000-000, 2021.
Background:
Systemic intermittent hypoxia therapy (IHT) has been shown to elicit beneficial effects on multiple physiological systems. However, only few studies have investigated the effect of long-term normobaric IHT on bone mass and mechanical and microstructural properties. The aim of the present study was to examine the effect of IHT on bone in both healthy and osteopenic mice.
Materials and Methods:
Thirty mice were stratified into four groups: Ctrl, Ctrl+IHT, Botox, and Botox+IHT. Osteopenia was induced by injecting Botox into the right hindlimb of the mice causing paralysis and disuse. IHT animals were placed in a normobaric hypoxia-chamber (10% oxygen) for 1 hour twice daily 5 days/week. Animals were sacrificed after 21 days, and DEXA, micro-computed tomography, and mechanical testing were performed on the femora.
Results:
As expected, Botox resulted in a significant reduction of bone mineral content (-23.4%), area bone mineral density (-19.1%), femoral neck strength (Fmax: -54.7%), bone volume fraction (bone volume/tissue volume: -41.8%), and trabecular thickness (-32.4%). IHT had no measurable effect on the bone properties in either healthy or osteopenic mice.
Conclusion:
The study confirmed that Botox led to loss of bone mass, deterioration of trabecular microstructure, and loss of bone strength. These changes were not influenced by IHT. Notably, IHT had no detrimental effect on bone in either healthy or osteopenic mice. This indicates that IHT of ailments outside of the skeletal system may be administered without causing harm to the bone.
Immobilization osteoporosis represents a wide spectrum of conditions and disorders. Bone loss due to immobilization is a consequence of reduction in mechanical load. The etiology and severity of the immobilizing condition, anatomical region, age, gender, genetic factors, and duration are a few considerations that determine the location, magnitude, and characteristics of the observed accelerated skeletal deterioration. After severe immobilization-related bone loss, risk of fracture is increased in the short-term or, if less severe, increased when associated with age-related skeletal changes. Currently, the clinical interventions prescribed to maintain bone for more severe forms of immobilization are often not efficacious. Animal models of immobilization, including those of limb casting, tenotomy, hindlimb unweighting, peripheral nerve transection, and spinal cord injury have afforded knowledge and insight into the cellular, biochemical, and molecular changes that occur with immobilization/disuse and have provided potential strategies to implement to reduce the bone loss related to reduction in load.
Bone is continuously remodeled in terrestrial vertebrates and aquatic mammals throughout life. Osteoclasts resorb mineralized bone matrix in a manner that mobilizes skeletal calcium, and osteoblasts then refill the resorption spaces with a collagenous matrix that incorporates extracellular calcium as it mineralizes and gains biomechanical stiffness. It is commonly assumed that one of the main purposes of this process is to renew bone matrix, which might promote biomechanical integrity by repairing microdamage or by other means. However, the preponderance of experimental data indicates that remodeling inhibitors increase rather than decrease bone strength in animals, while decreasing fracture risk in patients with low bone mass. In attempting to resolve this paradox, this chapter proposes that matrix renewal is not an important function of continuous bone remodeling and that calcium homeostasis is its original and primary purpose. Comparative biology suggests that remodeling originated in tooth-bearing bones of fish, the tetrapod descendants of which would apply the trait throughout their skeletons to provide a steady supply of calcium. The remodeling trait was coopted to serve other purposes, including skeletal repair and the elimination of underloaded bone tissue. Biomechanical benefits of remodeling are real but indirect, based on the refilling of resorption spaces that allows remodeling to serve metabolic imperatives while minimizing losses of bone strength.
The objective of this chapter is to describe the clinical evidence for and consequences of bone loss (osteopenia) associated with immobilization. Various methods have been used to examine the skeletal response to immobilization, including assays of biochemical markers of bone turnover, collection of histologic and histomorphometric data, and measurements of bone mass by rediographic and densitometric techniques. By use of these different measurement techniques, information has been obtained on the cellular, tissue, and organ level; however, historically, the choice of technique has usually been limited by availability. A continuum of human conditions of immobilization are presented in which bone atrophy has been observed, ranging from complete motor paralysis through reversible immobilization. Viewed together, the results from these studies provide evidence on the contributions of weightbearing and muscular activity in regulation of human bone response. There is much concordance of observed response among the different immobilization conditions, despite different methodologic approaches. Further, there are generally three approaches to quantifying skeletal response to immobilization: biochemical measurement of markers of bone metabolism, histomorphometric assessment of local bone activity, and regional analysis of bone mass or mineral content. Results from these different techniques are related but different processes and different scales of effects are represented. Biochemical assessment can identify the earliest response as initial alteration of bone metabolism occurs. Reversal or prevention of immobilization-related bone atrophy has been attempted by several means. These include simulation or resumption of weight bearing, stimulation of muscular contractions, and use of pharmaceutical agents. The former two approaches are clearly based on the assumption that the predominant factor underlying bone loss (directly or indirectly) is the elimination of “normal” mechanical loading through standing, walking and mucular activity.
Skeletal disuse can cause an accumulation of bone marrow adipose tissue (MAT) characterized by a combination of marrow adipocyte hyperplasia and/or hypertrophy. The malleability of MAT accumulation and of the hyperplasia and hypertrophy upon remobilization is unknown. In this study, we showed extensive hyperplasia and accelerated hypertrophy of bone marrow adipocytes in the proximal tibia epiphysis of rat knees immobilized for durations between 1 and 32 weeks. Similar histomorphometric measures of adipocytes carried out in unoperated controls allowed distinguishing the effects of immobilization from the effects of aging. While both knee immobilization and aging led to adipocyte hypertrophy, adipocyte hyperplasia was the hallmark signature effect of immobilization on MAT. Both bone marrow adipocyte hyperplasia and hypertrophy were sustained despite knee remobilization for durations up to 4 times the duration of immobilization. These results suggest that adipocyte hyperplasia is the predominant mechanism explaining MAT accumulation in skeletal disuse. In this model, the changes were unremitting for the investigated time points. Investigating the cellular and molecular mechanisms of marrow adipocyte mechanoregulation will be important to better understand how adipocytes adapt to changes in mechanical environments.
ABSTRACT Persons with neurologically motor‐complete spinal cord injury (SCI) have a marked loss of bone mineral density (BMD) of the long bones of the lower extremities, predisposing them to fragility fractures, especially at the knee. Denosumab, a commercially available human monoclonal IgG antibody to receptor activator of nuclear factor‐κB ligand (RANKL), may provide an immunopharmacological solution to the rapid progressive deterioration of sublesional bone after SCI. Twenty‐six SCI participants with subacute motor‐complete SCI were randomized to receive either denosumab (60 mg) or placebo at baseline (BL), 6, and 12 months. Areal bone mineral density (aBMD) by dual energy x‐ray absorptiometry (DXA) at 18 months at the distal femur was the primary outcome and aBMD of the proximal tibia and hip were the secondary outcomes analyzed in 18 of the 26 participants (denosumab, n = 10 and placebo, n = 8). The metrics of peripheral QCT (pQCT) were the exploratory outcomes analyzed in a subsample of the cohort (denosumab, n = 7 and placebo n = 7). The mean aBMD (±95% CI) for the denosumab versus the placebo groups demonstrated a significant group × time interactions for the following regions of interest at BL and 18 months: distal femoral metaphysis = mean aBMD 1.187; 95% CI, 1.074 to 1.300 and mean aBMD 1.202; 95% CI, 1.074 to 1.329 versus mean aBMD 1.162; 95% CI, 0.962 to 1.362 and mean aBMD 0.961; 95% CI, 0.763 to 1.159, respectively (p
A round-trip human mission to Mars is anticipated to last roughly three years. Spaceflight conditions are known to cause loss of bone mineral density (BMD) in astronauts, increasing bone fracture risk. There is an urgent need to understand BMD progression as a function of spaceflight time to minimize associated health implications and ensure mission success. Here we introduce a nonlinear mathematical model of BMD loss for candidate human missions to Mars: (i) Opposition class trajectory (400–600 days), and (ii) Conjunction class trajectory (1000–1200 days). Using femoral neck BMD data (N = 69) from astronauts after 132-day and 228-day spaceflight and the World Health Organization’s fracture risk recommendation, we predicted post-mission risk and associated osteopathology. Our model predicts 62% opposition class astronauts and 100% conjunction class astronauts will develop osteopenia, with 33% being at risk for osteoporosis. This model can help in implementing countermeasure strategies and inform space agencies’ choice of crew candidates.
Nutrition plays a multifaceted role during space flight. Although its most obvious function is maintaining general health through the consumption of required nutrients, the most important specific functions of proper nutrition are maintaining endocrine and immune system function, skeletal and muscle integrity, and hydration status of spaceflight crews. In addition, interpersonal interactions during mealtimes build team morale and enhance productivity. Providing high-quality, palatable foods is imperative for ensuring adequate nutritional intake, and careful assessment is required to monitor the success or failure of the food system and to ensure crew health. We believe that acknowledging the full role of nutrition will be of paramount importance to the success of extended-duration space missions.
Immediately after spinal cord injury (SCI), approximately 75% of patients suffer rapid and severe loss of bone mineral density (BMD) below the lesion level (i.e., sublesional), leading to osteoporosis (OP) in ~ 60% 1-year post-injury. The distal femur (DF) and proximal tibia (PT) are most commonly involved, and 70% of SCI patients sustain a low impact fracture at some point in their lifetime, adding disability to an already physically challenged population. Unfortunately, OP treatments for post-menopausal women are not as effective for OP post-SCI. Mechanisms of new agents targeting the neurogenic etiology of bone resorption (i.e., denosumab and anti-sclerostin antibodies) may hold greater potential and are discussed. Furthermore, standardized DXA protocols with normative BMD values for the DF and PT sites have not been established, so diagnosing OP is problematic. This review will summarize the pathophysiology of sublesional OP after SCI, the unique challenges of diagnosing and managing OP in SCI patients and provide recommendations for future studies. Given the Veterans Health Administration (VA) is the largest health care system in the world for persons with SCI, it is well-equipped to add to gaps in the literature.
In his 1966 treatise, “Post Traumatic Osteopenia,” Nilsson1 points out that the earliest observations of bone loss following trauma were made by von Volkmann in 1862 and Sudeck in 1900, describing what was called “Sudeck’s atrophy.” The latter syndrome, now generally called reflex sympathetic dystrophy (RSD), was characterized by a prolonged, painful recovery from trauma and associated with a loss of bone mineral in the injured extremity. During the early development of radiography, the local bone density loss in RSD was large and more likely to be seen. More refined radiographic techniques, however, have since revealed that osteopenia following fracture or trauma is much more common. Furthermore, it became apparent as early as 1950 that loss of regional bone mass after fracture is quite rapid, while at the fracture location itself bone density may increase due to the formation of the callus. Observations continued and became more quantifiable with the development of single-photon (radionuclide) absorptiometry (SPA) and eventually dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography (CT).² These noninvasive methods of regional bone densitometry have enabled measurements to be made in thicker regions of the body such as the proximal femur and spine, as well as more precise longitudinal measurements with time.
A reduction in trabecular bone mass is often associated with an increase in marrow fat in osteoporotic bones. The molecular mechanisms underlying this inverse correlation are incompletely understood. Here, we report that mice lacking tuberous sclerosis 1 (Tsc1) in Osterix‐expressing cells had a significant decrease in trabecular bone mass characterized by decreased osteoblastogenesis, increased osteoclastogenesis, and increased bone marrow adiposity in vivo. In vitro study showed that Tsc1‐deficient bone marrow stromal cells (BMSCs) had decreased proliferation, decreased osteogenic differentiation, and increased adipogenic differentiation in association with the downregulation of Wnt/β‐catenin signaling. Mechanistically, TSC1 deficiency led to autophagy suppression and consequent Notch1 protein increase, which mediated the GSK3β‐independent β‐catenin degradation. Together, our results indicate that Tsc1 controls the balance between osteoblast and adipocyte differentiation of BMSCs. This article is protected by copyright. All rights reserved
High-pressure lavage produces greater visible damage to bone at a macroscopic and microscopic level when compared with low-pressure lavage and can result in delay in the healing of fractures. Osteoblasts and adipocytes are derived from mesenchymal stem cells. Conditions which lead to bone loss often involve a switch from the osteoblast to adipocyte lineage. We have therefore examined the effect of high- and low-pressure irrigation on the differentiation of adipocytes.
Calvaria-derived bone cells were exposed to either low-pressure or high-pressure irrigation with normal saline. After 14 days the cells were fixed and the osteoblasts and adipocytes quantified using Oil Red O to stain cytoplasmic lipid droplets (triglycerides) in the cells. Osteoblasts were quantified using a commercially available alkaline-phosphatase staining assay.
A standard quantitative reverse transcription-polymerase chain reaction (RT-PCR) was performed. Messenger RNA levels for osteocalcin, a marker of osteoblasts, and PPARγ2, a marker of adipocytes, were measured. High-pressure lavage resulted in an increase in adipogenesis of 50% when compared with low-pressure lavage.
Our findings suggest that high-pressure lavage may promote differentiation of mesenchymal stem cells towards the adipoctye lineage. This may have clinical significance in the development of delayed and nonunion after treatment of fractures of long bones.
Muscle and bone masses are highly correlated and muscles impose large loads on bone. Muscle wasting that accompanies bone loss has been poorly investigated. 21 female mice were spread into seven groups. At day 0, 18 mice received Botulinum toxin (BTX) injection in the quadriceps muscle to induce paralysis of the right hind limb; the left contralateral side was used as control. Mice were sacrificed at 7, 14, 21, 28, 56 and 90 days post-injection. A remaining group was sacrificed at day 0. Trabecular bone volume was determined by microcomputed tomography (microCT) at the distal femur and tibia proximal metaphyses on both sides. Limbs were immersed in an HgCl2 solution allowing muscle visualization by microCT. On 2D sections, the cross-sectional areas and form-factors were measured for the quadriceps at mid-thigh and gastrocnemius at mid-leg and these muscles were dissected and weighed. Bone volume decreased in the paralysed side. Bone loss was maximal at 56 days followed by recuperation at 90 days. The cross-sectional areas of gastrocnemius and quadriceps were significantly lower in the paralysed limb from 7 days; the decrease was maximum at 21 days for the gastrocnemius and 28 days for the quadriceps. No difference in form-factors was found between the two limbs. Similar results were obtained with the anatomical method and significant correlations were obtained between the two methods. Quantitative analysis of muscle loss and recovery was possible by microCT after using a metallic contrast agent. Loss of bone secondary to muscle wastage induced by BTX and recovery showed a parallel evolution for bone and muscles.
Many studies of the response of isolated osteoblasts and osteoclasts to treatments exist. While such studies are informative, a reliable path to translating those effects into effects in humans is required, because of the skeletal intermediary organization that only exists in vivo. Bone cells function in vivo within the intermediary organizations of modeling, which controls bone growth and shape changes, and remodeling, which controls bone renewal during adulthood (Frost, Metab Bone Dis Rel Res 4:281–290, 1983). Modeling and remodeling govern how important tissue-level properties of the whole skeleton, such as bone mass, microarchitecture, strength, and calcium homeostasis, respond to treatment. Animal models are the lowest level at which the tissue-level intermediary organizations of modeling and remodeling can be examined. The purpose of this chapter is to give toxicologists an overview of some popular animal models of diseases of low bone strength, which can be used to translate basic research findings to the whole animal and human level. It focuses on osteoporosis and how various models not only provide in vivo skeletal behaviors that reflect tissue-level organizations found in adult humans but also can be applied to assist in understanding ways to prevent and treat various types of osteoporosis.
Spinal cord injury (SCI) causes rapid, severe osteoporosis with increased fracture risk. The pathogenesis of osteoporosis after SCI is a complex process and is usually attributed to “disuse” or “immobilization.” However, the exact pathophysiology of osteoporosis after SCI is still not clear. In SCI, bone remodeling becomes uncoupled with an initial decrease in bone formation and steadily increasing bone resorption. Osteoporosis after SCI can be evaluated by measuring BMD using DEXA, pQCT, and MRI; and estimating biochemical markers of bone turnover. Bone cell activity can be evaluated indirectly with techniques, such as specific serum and urine biochemical markers of bone turnover. An improved understanding of the natural history and risk factors for chronic bone loss following SCI is essential to designing therapies to reduce the rate of bone loss, define fracture risk, and ultimately prevent osteoporotic fractures and their associated morbidity. In conclusion, we are of the opinion that prospective randomized controlled trials should be conducted to evaluate, standardize, and find bone-specific biochemical marker of bone turnover, for the better understanding of the pathophysiology of osteoporosis in SCI.
Acute traumatic spinal cord injury (SCI) can result in rapid motor loss and inability to ambulate. Due to sudden immobility, increased bone turnover and eventual osteoporosis become prevalent in the first several months post injury. Forms of nontraumatic spinal cord injury also exist and are discussed briefly in this chapter as well as in areas of this text that cover the primary reasons for motor and sensory loss in these patients, including metastatic lesions to the spine with cord compression or demyelinating lesions in the spinal cord. In stark contrast to the sudden development of bone loss evident in both adult and pediatric traumatic SCI, spina bifida occurs at birth and demonstrates very different mechanisms. The distinctions among these conditions and the divergent approaches to treatment are discussed in this chapter.
Disuse induces a rapid bone loss in humans and animals; hypodynamia/sedentarity is now recognized as a risk factor for osteoporosis. Hypodynamia also decreases bone mass but its effects are largely unknown and only few animal models have been described. Hypodynamic chicken is recognized as a suitable model of bone loss but the effects on the quality have not been fully explored. We have used ten chickens bred in a large enclosure (FREE group); ten others were confined in small cages with little space to move around (HYPO group). They were sacrificed at 53 days and femurs were evaluated by microcomputed tomography (microCT) and nanoindentation. Sections (4 µm thick) were analyzed by Fourier Transform InfraRed Microspectroscopy (FTIR) to see the effects on mineralization and collagen and quantitative backscattered electron imaging (qBEI) to image the mineral of the bone matrix. Trabecular bone volume and microarchitecture were significantly altered in the HYPO group. FTIR showed a significant reduction of the mineral-to-matrix ratio in the HYPO group associated with an increase in the carbonate content and an increase in crystallinity (calculated as the area ratio of subbands located at 1020 and 1030 cm−1) indicating a poor quality of the mineral. Collagen maturity (calculated as the area ratio of subbands located at 1660 and 1690 cm−1) was significantly reduced in the HYPO group. Reduced biomechanical properties were observed at the tissue level. Confined chicken represents a new model for the study of hypodynamia because bone changes are not created by a surgical lesion or a traumatic method. Animals have a reduced bone mass and present with an altered bone matrix quality which is less mineralized and whose collagen contains less crosslinks than in control chicken.
Persons with spinal cord injury (SCI) undergo immediate unloading of the skeleton and, as a result, have severe bone loss below the level of lesion associated with increased risk of long-bone fractures. The pattern of bone loss in individuals with SCI differs from other forms of secondary osteoporosis because the skeleton above the level of lesion remains unaffected, while marked bone loss occurs in the regions of neurological impairment. Striking demineralization of the trabecular epiphyses of the distal femur (supracondylar) and proximal tibia occurs, with the knee region being highly vulnerable to fracture because many accidents occur while sitting in a wheelchair, making the knee region the first point of contact to any applied force. To quantify bone mineral density (BMD) at the knee, dual energy x-ray absorptiometry (DXA) and/or computed tomography (CT) bone densitometry are routinely employed in the clinical and research settings. A detailed review of imaging methods to acquire and quantify BMD at the distal femur and proximal tibia has not been performed to date but, if available, would serve as a reference for clinicians and researchers. This article will discuss the risk of fracture at the knee in persons with SCI, imaging methods to acquire and quantify BMD at the distal femur and proximal tibia, and treatment options available for prophylaxis against or reversal of osteoporosis in individuals with SCI.
Spinal cord injury (SCI) causes rapid, severe osteoporosis with increased fracture risk. The pathogenesis of osteoporosis after SCI is a complex process and is usually attributed to “disuse” or “immobilization.” However, the exact pathophysiology of osteoporosis after SCI is still not clear. In SCI, bone remodeling becomes uncoupled with an initial decrease in bone formation and steadily increasing bone resorption. Osteoporosis after SCI can be evaluated by measuring BMD using DEXA, pQCT, and MRI; and estimating biochemical markers of bone turnover. Bone cell activity can be evaluated indirectly with techniques, such as specific serum and urine biochemical markers of bone turnover. An improved understanding of the natural history and risk factors for chronic bone loss following SCI is essential to designing therapies to reduce the rate of bone loss, define fracture risk, and ultimately prevent osteoporotic fractures and their associated morbidity. In conclusion, we are of the opinion that prospective randomized controlled trials should be conducted to evaluate, standardize, and find bone-specific biochemical marker of bone turnover, for the better understanding of the pathophysiology of osteoporosis in SCI.
Decreased bone formation is often associated with increased bone marrow adiposity. The molecular mechanisms that are accountable for the negative correlation between bone mass and bone marrow adiposity are incompletely understood. Focal adhesion kinase (FAK) has critical functions in proliferation and differentiation of many cell types; however, its roles in osteoblast lineage cells are largely unknown. We show herein that mice lacking FAK in Osterix-expressing cells exhibited decreased osteoblast number and low bone mass as well as increased bone marrow adiposity. The decreased bone mass in FAK-deficient mice was accounted for by decreased proliferation, compromised osteogenic differentiation, and increased adipogenic differentiation of bone marrow Osterix-expressing cells resulting from downregulation of Wnt/β-catenin signaling due to the reduced expression of canonical Wnt ligands. In contrast, FAK loss in calvarial preosteoblasts had no adverse effect on their proliferation and osteogenic differentiation and these cells had intact Wnt/β-catenin signaling. This article is protected by copyright. All rights reserved.
Osteoporosis, the most common metabolic bone disease, is by definition a systemic skeletal disease characterised by low bone mass and microarchitectual deterioration of bone tissue, with resultant increase in bone fragility and susceptibility to fracture. While primary osteoporosis is a condition of reduced bone mass appearing in postmenopausal women (postmenopausal osteoporosis) and in elderly individuals (senile osteoporosis), secondary osteoporosis is a condition of reduced bone mass resulting from a variety of specific and well-defined disorders, such as thyrotoxicosis, glucocorticoid use, and immobilisation (Table 9.6).
Accretion and resorption of the skeletal mass, especially of the lower part of the body, are maintained in equilibrium by the stimulus of weight bearing and activity. Immobilization, whether by prolonged recumbency, paralysis, or space-flight immobilization, leads to bone atrophy. Calcium released by the immobilized skeleton is excreted in the urine with resulting hypercalciuia ultimately reflecting the extent of bone loss. The excessive elimination of calcium salts in the urine also predisposes to nephrocalcinosis and nephrolithiasis, the latter representing a frequent complication of spinal-cord lesions. The deposition of calcium salts in soft tissues is another sequela of loss of calcium from the skeletal mass.
This chapter presents an overview of the physiologic changes associated with bed rest and major body injury. Bed rest is routinely, and often casually, prescribed for a wide variety of pathophysiologic states, the rationale being to reduce functional demands on a diseased body. Many studies, utilizing a wide variety of experimental subjects and of protocols, have been undertaken to examine the cardiovascular effects of prolonged immobilization. Many investigators have noted orthostatic intolerance after prolonged bed rest. They attributed this, in part at least, to the intravascular volume depletion, possibly compounded by an increase in venous pooling in the lower extremities because of increased venous compliance after bed rest. In addition to the changes in intravascular volume and venous tone, prolonged recumbency blunts cardiac responsiveness to rapid changes in posture. Bed rest increases the resting pulse from 4 to 15 beats per minute, and after bed rest, there is a more pronounced increase in heart rate with exercise.
Over 300 years ago Galileo and Vesalius suspected skeletal architecture might depend on mechanical usage [1] and more than 100 years ago Julius Wolff stated the relationship between bone function and its architecture [2]. Therefore, the effects of reduced mechanical usage on bone have been known for a long time. In 1924, J.W. Dowden wrote: “the musculature of a limb is reflected in the bones, so that it is easy to distinguish the long bone of a strong man, by its solidity and powerful ridges for muscular attachment, from the bone of a disuse limb, by the lightness and smoothness of the latter. The results of disuse are rapidly seen, even in the X-ray photographs” [3], In 1941, Albright and colleagues reported the case of a young boy who developed hypercalcemia as a consequence of the immobilization for a fracture. During the 1940s and 1950s, alterations in calcium and phosphorus metabolism were described by Whendon and colleagues in poliomyelitic patients and immobilized volunteers and an elevated rate of bone turnover after fracture was described by Bauer [4] and confirmed by others [5,6].
Total joint replacement remains one of the most commonly performed and successful procedures in modern orthopaedic surgery. Reported long-term success rates above 95% in many large case series have led to a steady increase in popularity with more than 1 million joint replacement procedures performed annually worldwide.¹ Considering the aging population, this number should continue to increase as most joint replacements are performed in patients over 65 years of age. Numerous outcome studies have documented the utility of joint replacement by significant improvements in both functional status and quality of life.
The term secondary osteoporosis is generally used when bone loss is induced by specific and well-defined conditions. These conditions include the following:
Drug-related
Glucocorticoids
Heparin
Oral anticoagulants
Thyroid hormone
Methotrexate
Lithium
Gonadotrophin-releasing analogs
Anticonvulsants (?)
Endocrine disorders
Hyperthyroidism
Hypercorticolism
Diabetes mellitus
Hypogonadism
Hyperparathyroidism
Gastrointestinal disorders
Gastrectomy
Inflammatory bowel disease
Malabsorption syndrome
Marrow disorders
Leukemia
Lymphomas
Systemic mastocytosis
Plasma cell dyscrasia
Anemias
Connective tissue disorders
Osteogenesis imperfecta
Ehlers-Danlos syndrome
Marfan syndrome
Rheumatoid arthritis
Miscellaneous
Immobilization
Alcohol abuse
Anorexia nervosa
Pregnancy, lactation
Chronic neurological disease
Hyperphosphatasia
Malignancy
Cadmium poisoning
According to the statement provided by two consensus conferences, osteoporo?sis may be defined as a disease characterized by low bone mass and microarchitec?tural deterioration of bone tissue, leading to enhanced bone fragility and a conse?quent increase in fracture risk [1, 2]. From a practical point of view, diagnostic criteria for osteoporosis for clinical use include the presence of fractures (spine, distal forearm, hip) or a value for bone mineral density (BMD) or bone mineral content (BMC) that is more than 2.5 SD below the young adult mean value [3]. Cer?tainly not all disorders listed above are able to give rise to a condition of osteoporo?sis but may cause only osteopenia or low bone mass, with BMD or BMC 1–2.5 SD below the young adult mean value [3]. In this chapter we describe the features of bone loss of the most common types of secondary osteoporosis.
Although there has been a fairly clear understanding of what is meant by ‘osteoporosis’ for many years, there is some potential for confusion with the terms currently in use. Collins (1966) considered osteoporosis to be a generalised form of atrophy of bone, while reserving the actual term ‘bone atrophy’ for a more localised process, such as might occur in a paralysed limb. The term ‘localised osteoporosis’ is, however, frequently used to describe the changes in disused limbs or around severely arthritic joints. Sissons (1955) defined osteoporosis as a structural change in bone in which the supporting tissue is reduced in amount while remaining highly mineralised, and McLean and Urist (1961) thought in terms of increased bone porosity. The current general definition is of a disorder in which there is a diminution of bone mass without detectable differences from normal in the relative proportions of mineralised and non-mineralised matrix (Figs. 8.1, 8.2). Many workers prefer to use the term ‘osteopenia’ to describe this state of affairs and to reserve ‘osteoporosis’ for those cases of osteopenia in which there is actual or potential mechanical failure of bone. There is no general agreement as to the definition of either term and no difference in meaning is implied in the following account, though this might entail a more loose use of words than many would prefer.
To DISTINGUISH between osteitis fibrosa generalisata resulting from hyperparathyroidism and osteoporosis should, as a rule, be simple (1,2). Under one particular set of circumstances, however, the two conditions may closely simulate each other. It is the purpose of this paper to report one case in which an erroneous diagnosis was arrived at because the authors were not aware of certain points which this case illustrates.
To avoid confusion as to terminology the following rather dogmatic classification of metabolic bone conditions associated with demineralizjation is here inserted. The structure of bone tissue is constantly undergoing change. There are surfaces where bone is being resorbed and where one sees osteoclasts; there are other surfaces where the organic matrix is being laid down by the osteoblasts and where calcium saltsare being deposited into it from the tissue fluids. A diminution in the bony mass may result from either an increase of bone resorptionor a decrease of bone formation. The former condition is termed osteitis fibrosa generalisata and is met with in hyperparathy roidism; the latter must be further subdivided. Thus a decrease of bone formation may result either from an underactivity of the osteoblasts in laying down the organic matrix or from a failure in the deposition of the inorganic calcium salts into the organic matrix; the former condition is termed osteoporosis, the latter osteomalacia.
Thesis (doctoral)--Université Claude Bernard, 1972.
Spinal Cord is the official journal of the International Spinal Cord Society. It provides complete coverage of all aspects of spinal injury and disease.
Disuse bone atrophy was induced in 10 adult dogs by means of brachial plexus section and/or elbow disarticulation. After 9 to 12 weeks of disuse intact humeri were examined by X-ray, and their physical properties determined. Thewhole humeri were isolated, defatted, dried to constant weight, and their mineral and collagen content determined.
Eight out of 10 experimental (non-used) humeri demonstrated evidence of decreased radiodensity. The non-used limb demonstrated parallel loss in dry, fat-free weight (−23.2%), in collagen (−25.3%), and in mineral (−26.1%), as compared to the normal limb. The data indicated that the major portion of the lost bone tissue in disuse osteoporosis is replaced by water, fat, and other unidentified organic materials rather than fibrous tissue, and that collagen is lost in equal proportion to mineral. The proportionatelly greater loss of collagen and mineral than of dry, fat-free weight appears to be due to an increase of non-collagenous, non-lipid organic material, presumably protein.
An effort was made to perform complete metabolic balance studies of 2 astronauts during a 10-day pre-flight control phase, 14 days of orbital space flight (NASA Gemini-VII), and 4 days of post-flight recovery phase, measuring dietary intakes and excretions of calcium, magnesium, phosphate, sulfate, nitrogen, sodium, potassium and chloride. In addition, urinary excretions of 17-hydroxycorticosteroids, aldosterone and catecholamines were measured in the same subjects. Technical or engineering constraints on biomedical observations during the flight prevented optimal performance during the in-flight phase, resulting in variations in dietary control (except for calcium, which was reasonably constant) and in losses of urine samples. Considerable interindividual variability was demonstrated in all experimental indices measured. In one man, significant increases in urinary calcium occurred during the second week of flight, and persisted during the recovery phase; calcium balance became less positive in ...
Evaluations of bone mass changes in terms of calcium hydroxyapatite equivalency have been made for the central section of the os calcis and for hand phalanx 5-2 of men participating in seven bed rest units consisting of an equilibration period, a 14-day bed rest period, and a reconditioning period, with the level of calcium intake during bed rest ranging from 300 to 2,000 mg daily. The same type of bone mass determinations was made on the crews of the Gemini IV, Gemini V, and Gemini VII missions. The method of radiographic bone densitometry was used in evaluating skeletal changes in both groups of subjects.
A significant negative coefficient of correlation was found between bone mass losses in the central section of the os calcis and the mean levels of daily calcium intake after 14 days of horizontal bed rest. Significant positive correlations were found between intake of dietary calcium and outgo of urinary and of urinary and fecal calcium.
In four bed rest units in which the same level of dietary calcium was fed in the prebed rest ambulatory equilibration period as during the bed rest phase, the urinary and the combined urinary and fecal calcium output during bed rest surpassed that during ambulation by significant differences throughout.
With respect to the three groups of astronauts, the duration of the orbital flight evidently was not the sole factor in losses of bone mass, since the astronautts engaged in the longest space flight experienced the lowest negative changes in bone density.
Although mean daily calcium consumption was found to be related negatively to bone density losses in subjects during bed rest, the same could not be stated unequivocally concerning astronauts during space flight with the evidence now in hand because of uncontrolled variables, such as stress and dietary factors in addition to calcium. Also the exercise program introduced into the Gemini VII flight imposed a new variable which contributed to the reduction of bone mass in the os calcis as supported by ground based trials with bed rest subjects.
Because of the small number of subjects in the space flight study to date, further data will need to be acquired from future flights in order to understand the interrelationships more fully.
Combined calcium balance and radioactive calcium turnover studies have been performed in a series of normal and paralyzed adults. The purpose of this investigation was to evaluate the kinetic factors responsible for disuse osteoporosis.Patients with acutely developing disuse osteoporosis were found to have bone formation rates from normal to twice normal and bone resorption rates from two to three times normal. The increased bone resorption rates more than accounted for the negative calcium balances of these subjects. Patients with chronic, stable (but severe) disuse osteoporosis were found to be in calcium equilibrium, with bone formation and resorption rates either normal or slightly low. These observations indicate clearly that the absence of mechanical stresses did not, of itself, reduce bone forming activity, and that a primary increase in bone resorption was responsible for the development of disuse osteoporosis. In vivo uptake measurements of Sr85 in one subject confirmed the kinetic observations, to the effect that a more severely paralyzed extremity took up more isotope than did its less severely involved mate.Treatment of five of the paralyzed subjects with anabolic steroids produced the expected improvement in calcium balance, but kinetic analysis indicated that in the acute group the effect was entirely anticatabolic: i.e., there was no increase in bone forming activity, but a considerable decrease in bone resorption.Measurement of gastrointestinal calcium absorption in all subjects studied revealed gross depression of absorption efficiency in the acute stage of osteoporosis. This change, together with elevations in both serum calcium and serum phosphorus, are interpreted as indications of suppression of endogenous parathyroid function. As such, this evidence precludes any possible role of parathyroid hormone in the genesis of disuse osteoporosis.
1. The effect of immobilisation on bone formation has been investigated in the rat. As chlortetracycline has the property of being deposited preferentially in areas of newly deposited bone, its uptake can be used as a reflection of osseous formation.
2. One hind limb of albino rats was immobilised either by section of the second, third and fourth lumbar nerve trunks or by section of tendo calcaneus and ligamentum patellae. The incorporation of chlortetracycline was determined quantitatively in the femur and tibia of both hind limbs at intervals after immobilisation.
3. Tetracycline uptake is expressed in terms of bone weight, this being most important in order to obtain correct values.
4. A comparison between the tetracycline uptake and the weight of the bones gives information about the rate of bone destruction.
5. In animals immobilised by nerve section three phases can be distinguished: a first phase with diminished bone formation, a second with increased formation and increased destruction and a third phase with diminished bone formation. Both mechanisms, decreased formation and increased destruction, are therefore important in the production of immobilisation osteoporosis; their relative importance depending upon the duration of the immobilisation.
6. In animals immobilised by tendon section the mechanical function becomes restored in the second week as a result of healing: this explains the rapid compensation for the initial loss of weight of the bones accompanied by a marked increase in tetracycline uptake.
7. These results are discussed and compared with information in the literature. Variations in bone formation and destruction rates with time could explain the varied results reported by other authors.
A new procedure is described for the simple, rapid, quantitative measurement of serum alkaline phosphatase. The procedure is based on the direct photometric measurement of phenolphthalein released from sodium phenolphthalein phosphate. The substrate is available in a convenient, stabilized form as a tablet containing buffer and substrate in optimum amounts for a single analysis. As many as 30 analyses can be performed in an hour.
Bony manifestations of thyrotoxicosis Physiological senile involution and pathological rarefaction of bone. Quantitative and comparative histological data Quantitative bone histology as applied to the diagnosis of hyperparathyroid states. Clinical aspects of metabolic bone disease
- Vienna Meunier
- P Bianchi
- .-S Edouard
- C Bernard
- J Courpron
- P Vignon
- G Meunier
- P Courpron
- P Edouard
- C Bernard
- J Bringuier
- J Vignon
- G Meunier
- P Vignon
- G Bernard
- J Edouard
- C Courpron
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Bone atrophy in the paralyzed limb and. attempted arrest Clinical investigation of bone metabolism in spinal cord lesions Correlation of bone resorption and formation behavior of loaded bone
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Bone loss as a result of immobilization and chelation, preliminary results in Macaca mulatta Rapid method for the quantitative determination of serum alkaline 10hosphatase
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The reversibility of disuse osteoporosis Experimental studies in the adult rat Use of an image analysing computer for the study of osteocytic behavior in bone diseases
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The influence of immobilization of bone formation as evaluated by osseous incorporation of tetracycline Mineral electro-lyte and nitrogen balance studies of the Gemini-VII fourteen day orbital space flight Effects of recumbency and space flight on bone density. Amer
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Bone atrophy in the paralyzed limb and attempted arrest
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Utilisation de régression curviligne multiple pour la recherche d’interaction entre plusieurs facteurs quantitatifs
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La détermination complexométriquodu calcium sérique. Proposition d’une technique de dosage direct
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Bone remodeling and metabolic bone disease
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Données histologiques quantitatives sur le vieillissement osseux humain
- P Courpron
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- C Edouard
- J Bernard
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- G Vignon
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Enquête clinique et anatomique sur l’étiopathogénie de l’ostéoporose sénile
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