Wheelchair used indoors and outdoors, requirement of physical assistance of another person, with or without a walking aid, to walk short distances indoors
2. Walks with assistance
Wheelchair used to mobilize outdoors but independently mobile indoors without aid
Determined by number of packs per day and years at that rate
Includes current and previous prescriptions for antipsychotic or antiepileptic drugs
Fragility fracture history
Relates to additional fracture risk and increased osteoporosis because may cause decreased mobility
Higher risk in females over males
Higher risk in those with darker skin
Pathophysiology of Bone Metabolism After TBI
Most of the investigations of bone metabolic abnormalities following TBI have not focused on osteoporosis but rather on heterotopic ossification (HO), a process by which new bone is formed along with bone marrow in locations and tissues that normally do not ossify. These areas are typically found near but not within joints, generally the hip and shoulder following traumatic brain injury. Measures of bone formation including osteocalcin, bone-specific alkaline (B-ALK) phosphatase, and procollagen N1 terminal propeptide (P1NP) have been noted to be lower in persons immediately following TBI relative to subjects with new fractures absent of TBI , but these levels may be higher than those of healthy uninjured subjects. Osteocalcin remained low over the 7-day observation period but P1NP increased after three days, findings similar to those observed in patients with fractures alone.
The accelerated fracture healing and osteogenesis in the form of HO is thought to be centrally regulated, perhaps accentuated in the presence of inflammatory markers like IL-6 . In an animal model that compared TBI without fracture to experimentally induced TBI, no pattern of enhanced osteogenesis was found, but rather a predisposition toward osteoporosis . At the time of injury, markers of bone formation and resorption were not significantly increased in TBI patients without associated fractures. However, both P1NP and CTX were higher in those with TBI one week after injury (p = 0.053 and p = 0.059) but levels failed to reach statistical significance. While small sample sizes could account for lack of significance, these factors may be only part of the cause. Radiographic evidence of the lumbar spine and both distal femurs had a significant decline in BMD at only one week, suggesting a very rapid bone loss brought on by immobilization and potential biochemical and endocrine changes that remain undefined .
In both adults  and children , interleukin 6 (IL-6) stimulates vasopressin secretion in the posterior pituitary, causing elevated levels of antidiuretic hormone (ADH). The syndrome of inappropriate antidiuretic hormone (SIADH) is prevalent after TBI  and results in hyponatremia. SIADH may adversely affect functional outcomes, depending on the severity, persistence, and response to treatment. Dimopoulou et al.  assessed morning samples of baseline IL-6 and tumor necrosis factor alpha (TNF-α) in participants who received a low-dose cortisol stimulation test once critical care issues had stabilized sufficiently for such a test. All 40 subjects met definitions of moderate to severe head injury. Results found that 15 % of subjects were classified as nonresponders to the low-dose stimulation test. The responders had levels of IL-6 that were nearly double the responders, indicating that IL-6 levels are fundamentally altered in those with pituitary dysfunction. In contrast, TNF-α levels did not differ statistically between responders and nonresponders. Adrenocorticotrophic hormone (ACTH) function was also assessed, and CT of the adrenals was obtained, with primary and secondary adrenal failure noted in the absence of direct adrenal trauma. Medications inducing a similar type of picture, but instead suggesting inflammatory cytokines including IL-6 could be responsible for alterations in hypothalamic–pituitary–adrenal (HPA) axis.
The relationship of IL-6 and its link to SIADH is critical if not clinically corrected early in the hospital course. Hyponatremia is one consequence of sustained SIADH. A recent study examined 5,122 men from the Osteoporotic Fractures in Men study and found statistically significant increases in both vertebral and hip fractures among those with hyponatremia, defined as serum sodium <135 . Specifically, the fully adjusted model accounting for all confounders found that prevalent morphometric vertebral fractures, incident morphometric vertebral fracture, hip fracture, and other nonspine fracture were all increased in men with hyponatremia. An earlier large prospective study from Rotterdam showed that even mild hyponatremia can increase risk of nonvertebral fractures, but a relationship to vertebral fractures was less certain . This investigation differed from that of Jamal in that the study population was 50 % female and 8 % male. The lower percentage of males may explain why only 1.6 % of the study group demonstrated hyponatremia .
There are a number of possible explanations for why hyponatremia may increase risk of fractures. Falls have been linked to hyponatremia by causing gait instability, balance issues, and decreased attention. In the investigation by Jamal and colleagues , 31 % of the men with hyponatremia reported falls in the 12 months prior to assessment, compared to 21 % of those with normal serum sodium levels. Animal data has shown that sustained hyponatremia of longer than 90 days resulted in a 30 % reduction in femoral BMD in rats, relative to animals with normal sodium levels . Findings demonstrating a relationship between hyponatremia and osteoporosis, with and without the presence of fractures, have also been shown in human studies [12–16] but are subject to many confounding variables including thiazide diuretic use, other medications predisposing to falls, uncertain cardiac conditions with arrhythmias contributing to falls, and underreported drug or alcohol use.
Endocrine factors also predispose to bone loss following TBI. Posttraumatic hypopituitarism (PTHP) is a frequent occurrence following TBI. Recent estimates are that PTHP affects 28–35 % of newly injured patients [17, 18] and 36–68 % of those with chronic TBI of 3–30 years [19–21]. Dysfunction in the hypothalamic–pituitary axis contributes not only to compromised bone health but also to control of emotion, regulation of body temperature, blood glucose control, muscle strength, cognition, and reproductive function . PTHP results in a number of secondary endocrine abnormalities, many of which lead to increasing bone loss or predispose a patient to fracture. Because a number of the deficits are similar to the conditions seen in patients with TBI absent of PTHP, it can be difficult to determine the primary cause of functional, cognitive, and emotional outcome measures. Table 2 [6, 8, 9, 22–25, 41, 51] summarizes the specific endocrine abnormalities patients experience due to PTHP. These studies discuss PTHP in several contexts, unrelated to TBI.
Endocrine abnormalities following PTHP
Frequency after TBI
Study specific notes
Relation to osteoporosis or fractures
Glucocorticoid deficiency/ACTH deficiency
11.8 % (range 0–47 % with varying definitions and times of evaluation)
Acute: first month
Chronic: years after TBI
Life threatening (bed rest immobility)
Fatigue, weakness, decreased attention and concentration, predisposition to falls due to inattention, lack of strength
Bonadenelli M. et al. 
28.8 % (range 2–62 %)
Men: low testosterone
Women: low estrogen
Accelerated osteoporosis in combination with reduced peak bone density in younger men and women; in addition low testosterone is associated with fatigue, muscle atrophy, anhedonia, decreased estrogen with reduced motor processing speed, reaction time, and vigilance
Dimpopoulo I. et al. 
Clark JD. et al. 
Woolf PD. et al. 
Starts at day two post TBI and lasts at least two months but persists in many patients
Growth hormone deficiency
30 % (range 14.6–60 %)
Generally seen in acute phase
Muscle atrophy, fatigue, poor concentration—leading to greater fall risk
Masel BE.et al. 
18.5 % (range 3.6–31 %)
Review article summarizing several studies
Fatigue, muscle wasting, decreased attention and memory
Misra M. et al. 
Review article summarizing several studies
Stimulated bone resorption
SIADH (if associated with hyponatremia)
20 ± 10 %
Review article summarizing several studies
Increased fracture risk
Given the challenges of decreased balance, aggression, impulsivity, and unpredictable muscle weakness, patients with acute TBI are clearly at increased risk for falls. Exercise programs may contribute to prevention efforts, but to be most effective for osteoporosis prevention, they must be easy to follow, incorporate weight-bearing as well as aerobic fitness, and recognize cognitive and physical endurance limitations of these patients. Schwandt and colleagues found that aerobic exercise with hand cycles had a positive impact on depression reduction in subjects with TBI . Other authors have found similar results [26, 27]. Many of the studies selected modes of exercise that did not involve weight-bearing such as seated bicycling, hand cycle ergometry, or swimming [26, 28]. In general, aerobic exercise properly chosen may have benefits in physical and emotional health following TBI.
Banham-Hall and colleagues  recommend that an exercise program in TBI patients to decrease osteoporosis should have the following elements:
Intensity of exercise should be moderate to high.
Exercises should target sites of common fracture (hips, spine, ankles, wrists).
Exercises should have low impact such that one leg is firmly on the ground at all times.
Exercise should progress gradually from a comfortable level to a more intense level.
In addition to the above features, duration of exercise must take into consideration each patient’s physical and emotional tolerance, particularly in those with tendency toward violent or impulsive behavior. The exercise regimen should be simple and time limited. Doing an activity for hours at one time may not be conducive to learning or participation. Although variety may help patients with practicing cognitive goals of divided attention and task switching, a more basic program involving a component of repetition is frequently preferred, particularly given difficulties with new learning in patients with TBI. Some aspect of vestibular retraining is also advisable since TBI may impair a patient’s ability to utilize normal righting reactions in an effort to prevent fall.
One of the greatest challenges with any exercise program is compliance. Short-term memory deficits and psychological resistance based on mood could deter participation on any given day. Secondly, finding an appropriate venue in which to undertake an exercise program can be problematic. A gym or training center with loud music or many people could be too stimulating for some patients and lead to increased anxiety, agitation, and panic. Home settings may not be safe due to inadequate space for moving around, inappropriate flooring for seated stretching activities, or lack of devices for support during standing balance activities. Finally, the TBI patient benefits best from similar daily activities, so a twice weekly program may be inadequate. A daily program would be preferred, but available help for such a program is limited by family skill set and availability and by insurance caps for outpatient therapy visits. If chosen and accessible to patients, an outpatient therapy center should assist the patient with attendance by phone call reminders or text messages prior to each meeting.
Given the benefits of hormonal correction for subjects experiencing panhypopituitarism, supplementation with estrogen, progesterone, or testosterone would favor a preservation of bone density. Adopting a strategy of giving one of the above hormones in an effort to prevent a “future health problem” of osteoporosis and fracture prevention is a difficult task for patients to accept given the many other medications they take for immediate medical concerns. If supplementation with progesterone or estrogen has benefits for recovery of TBI while also protecting bones, patients may be more willing to consider their use in the weeks and months immediately following injury.
Selective Estrogen Receptor Modulators
Selective estrogen receptor modulators (SERMs) have been successfully used as a treatment for osteoporosis in women. Raloxifene, one of the older and most tested SERMs, can reduce reactive gliosis after TBI  and, in one report, improved sensorimotor function and reduced working memory deficits after bilateral cortical contusions . Evidence from studies on postmenopausal women, without a TBI, also suggests raloxifene may help in preventing cognitive decline  and improving verbal memory .
In terms of actual neuroprotection following TBI, a number of animal models suggest that selected SERMs including raloxifene promote axonal growth and the expression of synaptic markers, with the thought that such actions may contribute to health of functional circuitry and repair of damaged neural connections following injury from TBI . In additional models, examining levels of endorphin and tetrahydroprogesterone are increased in rats who receive raloxifene. While it is unclear if similar mechanisms exist in humans, basic science studies by Genazzani et al. as well as Bernardi et al. [34–36] imply that raloxifene can modulate local levels of neuroactive substances in the brain and, in doing so, influence synaptic function of neurons .
Along with estrogen, progesterone plays an important role in maintaining bone health in post- and perimenopausal women. Progesterone and estradiol control actions of both RANK and RANKL which independently play an essential part in bone metabolism. Reduced levels of progesterone stimulate RANK ligand to bind to RANK in a manner that upregulates osteoclastic function and promotes bone resorption. In this manner, progesterone plays a role in prevention of secondary osteoporosis. Following injury, some have proposed that progesterone prevents inflammation through inhibiting inflammatory cytokine production, reducing levels of complement factor C3, blocking activation of inflammatory-mediated microglial cells, and regulating vasogenic edema . Preclinical trials of progesterone in humans demonstrated promise in reducing mortality if administered within hours of injury [38, 39]. However, a follow-up investigation by Skolnick  did not demonstrate any significant difference in mortality outcome between those subjects receiving placebo and those receiving progesterone. Given this outcome, it is unlikely that patients with TBI will be eager to undertake progesterone as a treatment among other choices for osteoporosis prevention.
Bisphosphonates and Denosumab
Among bisphosphonates, denosumab, and other less potent options such as SERMs, practitioners may wish to strongly consider a treatment modality in which compliance can be effectively guaranteed. Options would include annual zoledronic acid 5 mg IV, denosumab 60 mg given twice annually via subcutaneous injection, or ibandronate 3 mg IV given every three months. All of the above are done in physician offices, ensuring that treatment is successfully achieved. Lack of compliance is a significant factor in outcomes of treatment programs among the patients without neurological disorders. For those with memory deficits, consistently taking medication and following directions for usage are even greater challenges.
Impact of Psychiatric Diseases on Bone Health
Prevalence, Pathophysiology, and Risk Factors
Psychiatric disorders as well as medications to treat psychiatric conditions are indicated in bone health conditions such as osteoporosis and osteopenia [40, 41]. Conditions such as autism spectrum disorders, bipolar disorders, borderline personality disorder, depressive disorders, and thought disorders such as schizophrenia have been studied and indicate risk factors for a decrease in bone mineral density (BMD) [41–43]. Medical treatments for these conditions, such as antidepressants, benzodiazepines, and antipsychotics, carry several side effects, including decreases in BMD [44–46]. In addition to BMD loss, other complications of psychotropic use include dyskinesias, orthostatic hypotension, as well as sedation, which can lead to an increase in risk of falls .
Many additional factors also affect BMD including age, race, gender, nutrition, and genetics other than psychiatric conditions and medications . Halbreich and Palter  also report that BMD may be due to decreased levels of estrogen and testosterone, decreased calcium, smoking, alcoholism, polydipsia, increased interleukin activity, impaired electrolyte and fluid balances, dietary imbalances, hypercortisolemia, and hyperprolactinemia. Comorbidities of these conditions in the psychiatric population can be quite high, especially due to immobility, poor health choices, lack of sunshine, and substance use [43, 46, 48]. The relationship between psychiatric conditions, medications, and bone health is unclear, but the neuroendocrine system has been shown to be impacted due to low bone turnover .
Autism Spectrum Disorders
Autism spectrum disorders (ASD) are a classification of disorders defined and characterized by behavioral disturbances including repetitive or restrictive interests or activities and difficulty with social communication . Attentional disorders, mental retardation, anxiety, depression, epilepsy, and obsessive-compulsive disorders occur frequently with ASD . These conditions can range from mild to severe impairment of functioning. Hediger et al.  studied 75 boys aged 4–8 years for metacarpal bone cortical thickness (BCT) and found that casein-free diet use, supplements, and medications had an impact on bone development. In particular, while study subjects and controls showed BCT levels to increase incrementally with age, there appeared to be a sharp deviation between the ages of seven and eight, indicating that dietary intake, specifically calcium and vitamin D (which are low in dairy-free casein diets), was almost twice that of controls with less restrictive diets. Researchers also concluded that other factors including lack of sunlight, low levels of physical activity, and other GI disorders led to a slowing of bone growth for this population [52–55].
Neumeyer et al.  also confirm that lower BMD in autistic children and adults leads to a significant increase in the hip, forearm, and spine fractures as studied from a large database of emergency departments in the United States. Their study concluded that factors such as lower amounts of physical activity, reduced vitamin D intake, as well as use of antipsychotic medications contributed to the findings. Roke et al.  add that long-term use of antipsychotic treatments for boys between the ages of 10 and 20 years with ASD shows an increase in hyperprolactinemia on BMD. This antipsychotic-induced hyperprolactinemia may affect bone turnover by the stimulation of bone resorption over bone formation as well as diminishing the development of sex hormones which leads to changes in bone metabolism. Filipek et al.  add that besides poor nutrition, medications to treat ASD often interfere with bone metabolism and suppress the appetite. Vitamin D deficiency was also found in studies of autistic children [58–60], and because of this, production of serum anti-MAG autoantibodies was implicated, leading to an autoimmunity concern for the study groups.
Bipolar disorders are classified as mood conditions that feature the presence of an occurrence of a manic episode and often a major depressive episode. Manic episodes are defined by a specific period of a persistently elevated, irritable, or expansive mood and at least three other symptoms including increased self-esteem or grandiosity, decreased need for sleep, pressure speech, flight of ideas or racing thoughts, being easily distracted, and an increase in goal-directed activity and risky behaviors. Depressive symptoms such as feeling sad or empty, anhedonia, weight loss, insomnia, fatigue, and feelings of worthlessness are often present. A mixed episode for bipolar disorders indicates that criteria are met for both a manic episode and a major depressive episode for nearly every day lasting at least one week . Several medications that are used to treat bipolar disorder have an impact on bone metabolism . In particular, lithium has a well-known association with hyperparathyroidism which leads to a suppression in thyroid-stimulating hormone (TSH) that impairs bone metabolism  as well as increases bone turnover and bone reabsorption . Misra et al.  also point out that anticonvulsants, often used as mood stabilizers to treat bipolar conditions, frequently show an association with osteopenia. Yang et al.  also support these studies showing that both lithium and mood stabilizers such as valproate reduce BMD. Their study of 19 subjects with bipolar disorder and therapy with valproate demonstrated that 47.4 % of the subjects showed a decreased BMD on DEXA scans and 22.3 % had osteoporosis in premenopausal women.
Borderline Personality Disorder
Borderline personality disorder (which is often diagnosed with major depressive disorder) shows a pattern of instability in personal relationships, poor self-image, marked impulsivity, and fears of real or imagined abandonment . There is no specific medical treatment for personality disorders, and borderline personality disorder often requires years of psychotherapy, including dialectical behavior therapy . Few studies have shown impact on BMD in individuals with psychiatric personality disorders. However, Kahl et al. [63, 64] researched bone loss in patients with borderline personality disorder along with major depressive disorder and show a possible association between cytokines that were able to activate osteoclastic cells. The researchers studied 22 patients with borderline personality disorder with and without comorbid major depressive disorder as well as 20 healthy volunteers. BMD was measured, and bone turnover and endocrine and immune determinations were included in the study. The results indicated that the subjects with borderline personality disorder along with major depressive disorder have significantly lower BMD than healthy subjects or those study participants with borderline personality alone. In particular, osteocalcin, serum cortisol, tumor necrosis factor (TNF), and interleukin-6 were significantly higher for the group with borderline personality disorder plus major depressive disorder versus the other two groups.
The researchers concluded that young women with borderline personality disorder along with comorbid major depressive disorder are at high risk for the development of osteoporosis and that borderline personality alone is not indicated as an independent risk for bone health. They further propose that immune and endocrine imbalances are the contextual factors for these findings [63, 64]. The researchers suggest their findings do not support previous hypotheses of vitamin D or estradiol deficiencies as well as alterations of bone metabolism as contributing factors to loss in BMD. They do, however, offer support for factors such as poor nutrition, neglect in childhood, and lack of support which are often contributing factors in major depressive disorder to overall health and possibly linked to lower BMD.
Affective disorders, including depression, can affect 5–10 % of the general population and are the most commonly described condition seen in clinical practice, second to hypertension [41, 65]. Aloumanis and Mavroudis  further add that depression and osteoporosis affect a large part of the population and the two have an impact on quality of life, morbidity, and life expectancy. Interestingly, these researchers also provide further evidence that depression impacts bone health at a higher degree than osteoporosis, affecting mood. Cizza et al.  support this concept by indicating that depression induces bone loss and fractures, due to immune and endocrine changes. Gebara et al.  also review criteria to summarize causation between depression and decreased bone density and show the influence of the neurotransmitter serotonin on bone health as well as a gradient of worsening bone health in correlation with worsening depression. Conversely, Wu et al.  report that depressive disorders and loss of BMD have inconsistent reports. They, in turn, completed a meta-analysis of 14 studies which found that decreased BMD and depression showed clinical significance, especially when related to bone loss of the spine and hip for women diagnosed with clinical depression. Misra et al.  show a strong association between lower BMD in both men and women who have affective disorders with neuroendocrine implications. Adjusting for conditions such as age, gender, activity, hormones, substance use, and lifestyle, depressive symptoms accounted for lower levels of osteocalcin and deoxypyridinoline (indicators for bone formation and reabsorption).