Disuse of the musculoskeletal system causes bone loss. Whether patients in vegetative state, a dramatic example of immobilization after severe brain injury, suffer from bone loss and fractures is currently unknown. Serum markers of bone turnover, bone mineral density (BMD) measurements, and clinical data were cross-sectionally analyzed in 30 consecutive vegetative state patients of a dedicated apallic care unit between 2003 and 2007 and compared with age- and sex-matched healthy individuals. Vegetative state patients showed low calcium levels and vitamin D deficiency compared with healthy controls. Serum bone turnover markers revealed high turnover as evidenced by markedly elevated carboxy-terminal telopeptide of type I collagen (β-crosslaps) and increased levels of alkaline phosphatase. BMD measured by dual-energy X-ray absorptiometry (DXA) scanning showed strongly decreased T- and Z-scores for hip and spine. Over a period of 5 years, 8 fragility fractures occurred at peripheral sites in 6 of 30 patients (n = 3 femur, n = 2 tibia, n = 2 fibula, n = 1 humerus). In conclusion, high bone turnover and low BMD is highly prevalent in vegetative state patients, translating into a clinically relevant problem as shown by fragility fractures in 20% of patients over a time period of 5 years. © 2014 American Society for Bone and Mineral Research.
Osteoporosis is a high-prevalence skeletal disorder characterized by low bone mass, microarchitectural bone disruption, and skeletal fragility, resulting in increased fracture risk. The importance of mechanical stress for skeletal integrity and bone mass has long been known. In disuse osteoporosis, bone loss is caused by prolonged skeletal unloading and reduction of mechanical stress, leading to decreased bone formation and uncoupling of bone resorption by involvement of various bone cells. Extended bed rest, para- and hemiplegia after spinal chord injury or stroke,[3, 4] and hypogravity are examples of long-term immobilization and mechanical unloading causing osteoporosis. In an aging society, bone loss causing increased fracture risk could become a major burden for elderly immobilized patients in terms of morbidity and mortality as well as health-care costs. Thus, prevention and therapy of this form of osteoporosis may become increasingly important. Data on fracture incidence without apparent external force in bedridden patients are currently limited. An observational study of patients in a long-term-care facility showed that 3.6% of 500 bedridden patients suffered spontaneous insufficiency fractures during a 6-year follow-up period.
Currently it is not known whether immobilized patients in vegetative state (VS), a dramatic neurological disorder characterized by a state of wakefulness without awareness after severe hypoxic brain injury, suffer from bone loss and fragility fractures. This study reports the results of the evaluation of osteological examinations, including measurement of bone mineral density (BMD), serum markers of bone turnover, and occurrence of low-trauma fragility fractures in 30 VS patients.
Materials and Methods
Thirty consecutive VS patients aged 20 to 71 years of the Apallic Care Unit at the Neurological Department of Geriatric Centre Wienerwald, Viennese Hospital Association, were retrospectively studied. All patients routinely received an osteological examination including measurement of BMD, serum bone turnover markers, and hormones between 2003 and 2007. Additionally, nontraumatic fragility fractures were recorded during this time period. Results were compared in a case-control study manner with randomly selected individuals from a population-based prospective study previously published.[7, 8] For the assessment of vitamin D level, calcium status, bone turnover markers, and bone mineral density, individuals were age- (± 5 years) and sex-matched. The study was approved by the Ethics Committee of the City of Vienna (EK 13-172-VK).
Bone mineral density and clinical chemistry
BMD was measured at the lumbar spine (L1 to L4) and the proximal femur at four different regions (femoral neck, trochanter, intertrochanteric area, and Ward's triangle) using dual-energy X-ray absorptiometry (DXA; Delphi, Hologic Inc., Waltham, MA, USA; coefficient of variation 1.0%) in all patients and controls. Consultant physicians and specially trained nursing staff ensured correct placement of VS patients for DXA scans. BMD data presented are derived from total lumbar spine and total hip measurements. Time between the event causing VS and osteological examination ranged from 0.4 to 21.1 years (mean 6.2 ± 5.1 years).
Serum parameters of VS patients and controls were obtained after overnight fasting and determined using standard laboratory methods. The following serum parameters were measured: calcium (mmol/L), phosphate (mmol/L), alkaline phosphatase (U/L), parathyroid hormone (PTH, pg/mL), 25(OH)Vitamin D (ng/mL), osteocalcin (ng/mL), β-crosslaps (ng/mL), total protein (g/dL), 17β-estradiol (pg/mL), follicle-stimulating hormone (FSH, mIU/mL), testosterone (ng/mL), cortisol (µg/dL), and thyroid-stimulating hormone (TSH, µIU/mL). β-crosslaps conversion from pmol/L to new units of ng/mL was done by using the equation x (ng/mL) = [y (pmol/L) – 138]/7750.
Data are presented as mean ± standard deviation (SD). Reported p values are the results of two-sided tests. Unpaired t test and chi-square test was used to compare unpaired data in the characterization of patients in VS. Data from patients in VS and the control group was compared using paired t test and chi-square test. Relations between age, sex, immobilization period, BMD values, serum bone turnover markers, and occurrence of fragility fractures were analyzed using point-biserial correlation coefficient and Fisher's exact test. Any p values <0.05 were considered statistically significant. Graphpad Prism (GraphPad Software Inc., La Jolla, CA, USA) and SPSS (SPSS Inc., Chicago, IL, USA) were used for statistical analysis.
Mean age of the 30 patients enrolled in this study was 45 ± 14 (range 20 to 71) years. Mean age of women was 48 ± 14 (range 20 to 71) years. On average, men were 5 years younger with a mean age of 43 ± 14 (range 25 to 63) years (Table 1). Intracerebral bleeding, hypoxic and traumatic events were responsible for VS in these patients. The event causing VS dated back 6.2 ± 5.1 (range 0.4 to 21.1) years at the time of osteological examination. Clinical characteristics and data on bone metabolism are presented in Table 1.
|All (N = 30)||Male (n = 16)||Female (n = 14)||p Valuea|
|Age (years)||45 ± 14||43 ± 14||48 ± 14||0.32|
|BMI (kg/m2)||21.5 ± 2.8||21.7 ± 2.8||21.3 ± 2.8||0.73|
|Duration of VS (years)||6.2 ± 5.1||6.0 ± 5.4||6.3 ± 4.9||0.89|
|T-score lumbar spine||–1.8 ± 1.5||–1.7 ± 1.9||–2.0 ± 0.9||0.54|
|Z-score lumbar spineb||–2.4 ± 1.1||–2.6 ± 1.2||–2.1 ± 0.9||0.36|
|BMD lumbar spine (g/cm2)||0.870 ± 0.168||0.911 ± 0.202||0.821 ± 0.101||0.16|
|T-score total hip||–3.0 ± 1.4||–2.4 ± 1.3||–3.8 ± 1.1||0.0033|
|Z-score total hipb||–3.1 ± 1.1||–2.7 ± 0.8||–3.7 ± 1.2||0.06|
|BMD total hip, g/cm2||0.581 ± 0.194||0.677 ± 0.197||0.478 ± 0.131||0.0036|
|Osteoporosis, n (%)||22 (73.3%)||10 (62.5%)||12 (85.7%)||0.26|
|Osteopenia, n (%)||6 (20.0%)||4 (25.0%)||2 (14.3%)|
|Normal T-score, n (%)||2 (6.7%)||2 (12.5%)||0 (0.0%)|
|Ca (mmol/L)||2.3 ± 0.1||2.3 ± 0.1||2.3 ± 0.1||0.91|
|P (mmol/L)||1.15 ± 0.15||1.10 ± 0.12||1.22 ± 0.16||0.0365|
|APase (U/L)||114.1 ± 39.4||116.9 ± 45.7||110.9 ± 32.1||0.68|
|PTH (pg/mL)||29.20 ± 14.51||25.10 ± 11.36||33.88 ± 16.63||0.10|
|25(OH)D (ng/mL)||19.74 ± 8.15||17.47 ± 9.18||22.54 ± 5.87||0.10|
|Osteocalcin (ng/mL)||30.69 ± 17.46||29.69 ± 17.66||31.83 ± 17.82||0.74|
|β-crosslaps (ng/mL)||0.98 ± 0.52||0.96 ± 0.50||1.00 ± 0.55||0.85|
|Total protein (g/dL)||6.8 ± 0.6||6.8 ± 0.6||6.7 ± 0.5||0.44|
|17β-estradiol (pg/mL)||40.7 ± 20.1||34.9 ± 10.6||47.4 ± 26.1||0.09|
|FSH (mIU/mL)||17.06 ± 19.02||12.26 ± 11.23||22.55 ± 24.51||0.14|
|Testosterone (ng/mL)||2.16 ± 1.68||3.37 ± 1.08||0.78 ± 1.06||<0.0001|
|Cortisol (µg/dL)||14.2 ± 7.6||14.7 ± 8.9||13.5 ± 5.8||0.68|
|TSH (µIU/mL)||1.60 ± 1.10||1.52 ± 1.26||1.69 ± 0.91||0.70|
25(OH)Vitamin D serum levels were adequate in only 1 of 30 patients according to current guidelines. Inadequate 25(OH)Vitamin D levels (20 to 29 ng/mL) or 25(OH)D deficiency (<20 ng/mL) was present in 13 (43.3%) and 15 (50.0%) individuals, respectively. Twenty-nine of 30 (96.7%) patients presented with massively elevated β-crosslaps levels, averaging 1.00 ± 0.51 ng/mL (reference range 0.04 to 0.40 ng/mL), whereas osteocalcin levels were in the normal range in the majority of patients.
Patients showed total hip T-scores averaging –3.0 ± 1.4 SD (range 1.5 to –5.1 SD) upon DXA imaging. For individuals younger than 50 years (male n = 11, female n = 8), mean total hip T-and Z-scores were –3.3 ± 1.0 SD and –3.1 ± 1.1 SD, respectively. In the lumbar spine, decrease in BMD was not as dramatic as in the hip, with mean T-scores of –1.8 ± 1.5 SD ranging from 2.1 to –5.1 SD. Mean lumbar spine T- and Z-scores of individuals younger than 50 years were –2.5 ± 1.1 SD and –2.4 ± 1.1 SD, respectively. According to the WHO diagnostic criteria based on DXA measurements, 22 (73.3%) patients showed osteoporotic T-scores, 6 (20.0%) patients classified osteopenic, whereas only 2 of 30 patients showed values in the range of healthy individuals. Thus, low BMD associated with high bone turnover is prevalent in VS patients.
Fragility fractures occurred in a significant proportion of patients (Table 2). Six of 30, all female, sustained fragility fractures including subtrochanteric (n = 2) and diaphyseal (n = 1) femoral fractures, combined tibial and fibular fractures (n = 2), and 1 humerus fracture. Female gender correlated highly with occurrence of fragility fractures (Fisher's exact test, p = 0.0051). Fractures occurred spontaneously or during routine care and were treated by surgical intervention (n = 2) or conservatively (n = 4). Mean age of the individuals affected by fragility fractures was 47 ± 18 (range 20 to 71) years with immobilization periods from 1.0 to 7.7 (mean 4.7 ± 2.8) years. Significant correlations between age, immobilization period, BMD results, serum bone turnover markers, and occurrence of fragility fractures in these patients were not found (data not shown).
|No.||Age at fracture (years)||Sex||Duration of VS (years)||T-score lumbar spine||T-score total hip||Osteocalcin (ng/mL)||β-crosslaps (ng/mL)||Fracture||Side||Treatment|
|1||49||F||7.2||–2.3||–3.3||23.80||0.69||Supracondylar femur fracture||Right||Scotchcast|
|3||35||F||7.7||–1.8||–4.7||18.04||0.52||Femur fracture||Left||Gamma nail|
|4||58||F||6.4||–0.9||–3.0||14.48||1.01||Infracondylar tibia fracture||Left||Scotchcast|
|Fibular head fracture|
|5||48||F||1.8||–1.7||–3.2||20.86||0.70||Pertrochanteric femur fracture||Left||Dynamic hip screw|
|6||18||F||1.0||–3.6||–5.0||35.27||1.23||Proximal tibia fracture||Right||Conservative|
|Proximal fibula fracture|
|Mean ± SD||47 ± 18||4.7 ± 2.8||–2.0 ± –0.9||–3.9 ± –0.8||24.23 ± 8.28||0.83 ± 0.26|
Next, we compared our findings in VS patients to an age- and sex-matched healthy control group (Table 3). VS patients had a significantly lower body mass index (BMI) than healthy controls, which is likely attributable to immobilization and altered nutrition. Serum analyses revealed elevated alkaline phosphatase and β-crosslap levels but lower calcium and total protein levels in VS patients compared with healthy controls. All other serum parameters available for both groups were similarly distributed. Both T-scores of the lumbar spine and femur were significantly lower in VS patients compared with healthy individuals.
|VS (n = 30)||Control (n = 30)||p Valuea|
|Age (years)||45 ± 14||46 ± 13||0.24|
|BMI (kg/m2)||21.5 ± 2.8||25.5 ± 4.3||0.0002|
|T-score lumbar spine||–1.8 ± 1.5||–0.1 ± 1.2||<0.0001|
|Z-score lumbar spineb||–2.4 ± 1.1||–0.3 ± 1.1||<0.0001|
|T-score total hip||–3.0 ± 1.4||–0.1 ± 0.9||<0.0001|
|Z-score total hipb||–3.1 ± 1.1||0.2 ± 1.1||<0.0001|
|Osteoporosis, n (%)||22 (73.3%)||0 (0.0%)||<0.0001|
|Osteopenia, n (%)||6 (20.0%)||9 (30.0%)|
|Normal T-score, n (%)||2 (6.7%)||21 (70.0%)|
|Ca (mmol/L)||2.3 ± 0.1||2.5 ± 0.1||<0.0001|
|P (mmol/L)||1.15 ± 0.15||1.17 ± 0.20||0.67|
|APase (U/L)||114.1 ± 39.4||76.6 ± 21.9||<0.0001|
|PTH (pg/mL)||29.20 ± 14.51||28.02 ± 17.00||0.79|
|25(OH)D (ng/mL)||19.74 ± 8.15||19.97 ± 11.68||0.84|
|Osteocalcin (ng/mL)||30.69 ± 17.46||21.71 ± 9.42||0.05|
|β-crosslaps (ng/mL)||0.98 ± 0.52||0.15 ± 0.10||<0.0001|
|Total protein (g/dL)||6.8 ± 0.6||7.4 ± 0.5||<0.0001|
To our knowledge, this is the first detailed analysis to address low BMD in VS patients apart from a single case report. This cross-sectional study of 30 patients in VS reports dramatically reduced BMD and occurrence of fragility fractures. Patients presented with low calcium levels, frequent vitamin D deficiency, serum bone turnover markers representing a high turnover situation, and DXA scans revealing strongly decreased T-scores especially at the hip, ultimately leading to fragility fractures in 20% of VS patients over a time period of 5 years.
Despite receiving enteral nutrition with monitoring of calcium, phosphate, and vitamin D intake, VS patients presented with lower calcium levels compared with healthy individuals, whereas vitamin D levels were comparably low. Serum bone turnover markers revealed high turnover as evidenced by markedly elevated carboxy-terminal telopeptide of type I collagen (β-crosslaps) and increased levels of alkaline phosphatase.
Under physiological conditions, a tightly regulated equilibrium between bone formation and resorption is maintained. Impaired bone integrity as a response to mechanical unloading is caused by uncoupling of bone remodeling, ie, simultaneous decrease in bone formation and increase in bone resorption.[1, 10] In the past years, the wnt/β-catenin signaling pathway has emerged as a key player in controlling bone homeostasis by regulating osteoblast differentiation and function. Upon skeletal unloading, osteocytes secrete sclerostin, a wnt/β-catenin pathway antagonist. By inhibiting wnt/β-catenin signaling, sclerostin is able to suppress osteoblast function, thereby mediating strain-related bone loss. Moreover, sclerostin seems to affect osteoclasts by influencing the receptor activator of NF-κB ligand (RANKL) to osteoprotegerin (OPG) ratio, resulting in bone resorption by stimulated osteoclast differentiation and activity. Sclerostin levels were shown to be elevated in immobilized patients and correlate with bone turnover markers. However, a recent study of patients with spinal cord injuries reveals a controversial role of sclerostin. Sclerostin serum levels seem to be initially increased in response to unloading but decrease over longer periods of immobilization because of reduction of sclerostin-secreting osteocytes in advanced bone loss. Whether these findings apply to our VS patients is currently unknown. We did not, however, observe a decrease in β-crosslaps in long-term immobilized VS patients.
From another pathophysiological point of view, altered brain metabolism and neuronal degeneration in VS patients might disturb the complex interactions between the central and peripheral nervous system and bone and could be considered as a contributing factor to bone loss, as reported for other neurological disorders.
Because of the inability of patients in VS to express pain, diagnostic procedures to confirm fragility fractures were carried out after appearance of redness and swellings in patients. Considering this obstacle, 8 fragility fractures were detected at peripheral sites in 6 of 30 VS patients over a period of 5 years. Fractures occurred independently of age or immobilization period and without any correlations to BMD at hip and spine or bone turnover markers. Interestingly, only women were affected by fragility fractures, the reason for this being currently unclear. Lower BMD might make women in VS more prone to fragility fractures during routine care. Incidence of fractures was 4.0% per year and mean immobilization period before fracture was 4.7 years in VS patients, compared with a previously reported yearly fracture incidence of 2.2% and mean time since injury of 8.9 years in 100 paraplegic men. Fractures occurred at the lower and upper extremities, including infracondylar and subtrochanteric femoral, infracondylar tibial, fibular head, and humerus fractures.
Although bone loss caused by long-term immobilization is reduced under antiresorptive therapy with bisphosphonates, new bone formation as reported for similar treatment of osteoporosis in postmenopausal women could not be shown. Nonpharmacological approaches for the management of disuse osteoporosis include electrical stimulation and vibration therapy. Although no data are available for immobilized patients in VS, reduced bone loss after electrical stimulation has been reported for patients with spinal cord injuries. Although first results look promising, more studies are necessary to evaluate the potential of these therapeutic approaches and translate them to clinical guidelines.
In conclusion, we show that VS patients commonly suffer from low BMD and fragility fractures. Currently, no clinical guidelines regarding prevention, diagnosis, and therapy of disuse osteoporosis in VS patients are available. Further studies are needed to better understand the pathophysiology of bone loss and to establish optimal treatment for these patients.
All authors state that they have no conflicts of interest.
We thank Valerie Nell-Duxneuner for statistical advice.
Authors' roles: Study design: JD, KK, and EZ. Study conduct: BO, GM, and EZ. Data collection: BO, GM, SK, and EZ. Data analysis: BO, SK, JZ, and EZ. Data interpretation: BM, JD, KK, JZ, and EZ. Drafting manuscript: BO and JZ. Revising manuscript content: BO, GM, BM, SK, JD, KK, JZ, and EZ. Approving final version of manuscript: BO, GM, BM, SK, JD, KK, JZ, and EZ. JZ takes responsibility for the integrity of the data analysis.