In this open-label non-randomised study, early musculoskeletal assessment was performed in patients with acute TSCI within 12 weeks of injury (compared with chronic TSCI patients 1–5 years post-injury). The acute cohort received early ZOL at baseline. Acute and chronic TSCI patients demonstrated different skeletal phenotypes at baseline, including higher markers of bone turnover and sclerostin concentrations in the acute cohort and mean ~ 20–30% lower hip and knee BMD in the chronic cohort. Despite early ZOL, acute TSCI patients experienced rapid mean ~ 15% hip BMD losses and even greater declines of ~ 20% at the knee over 4 years. BMD losses after acute TSCI led to osteoporosis in one patient although no fragility fractures occurred during follow-up. Preliminary data, albeit not significant, suggested more severe impairment (i.e., motor-complete lesion) may predict worse knee BMD response in the first 12 months after ZOL. APRs occurred frequently in acute TSCI patients receiving ZOL. Longitudinal assessment of the ‘natural history’ of osteoporosis in chronic TSCI patients was limited by insufficient data.

Patients with acute TSCI had higher serum phosphate concentrations. This is consistent with prior studies demonstrating higher serum phosphate and calcium and urinary calcium excretion and lower PTH in the first 6–12 months post-TSCI, potentially related to the exaggerated bone resorption [4, 6, 21, 22]. Although serum calcium was similar in our two cohorts, we did not assess ionised calcium or urinary calcium concentration, which may have revealed more subtle changes in calcium homeostasis. Acute TSCI patients in our study had higher serum markers of bone turnover, reflecting an exaggerated state of bone turnover in the acute state. It was previously suggested an uncoupling of bone resorption and formation may occur acutely after TSCI based on observations of markedly elevated bone resorption (e.g., deoxypyridinoline) and normal/mildly elevated bone formation markers (e.g., osteocalcin, total and bone-specific ALP) [4, 6, 22,23,24]. However, more recently, both CTx and P1NP have been shown to be elevated in acute SCI. A cross-sectional study found acute TSCI patients (n = 24) had CTx and P1NP concentrations at least double those in chronic TSCI (n = 38) and that higher concentrations correlated with shorter duration since injury [25]. Prospective studies have consistently shown CTx and P1NP are elevated in acute TSCI [26,27,28,29] with one study demonstrating a significant decline of P1NP over 24 months post-TSCI whilst b-ALP remained stable [26]. Similarly, in our study, baseline serum CTx and P1NP both correlated with shorter time since injury and strongly correlated with each other and hence may be more sensitive markers of bone turnover in acute TSCI. Small, randomised placebo-controlled studies have demonstrated a greater decline in bone turnover markers at 3–6 months post-injury in ZOL-treated patients, however, no difference at 1 year, suggesting earlier bone turnover marker response may be a useful marker of antiresorptive treatment effect in acute TSCI [26,27,28,29]. Although our study lacked a control group, our results are consistent since despite experiencing mean ~ 60% decline in CTx and P1NP within 1 year of receiving ZOL, patients with acute TSCI still lost considerable bone mass. The proportion of exaggerated bone turnover in acute SCI secondary to dysregulated skeletal homeostasis vs fracture healing is unclear. A retrospective study showed higher CTx in acute TSCI patients who sustained fractures during their injury or required skeletal surgery [30].

At study baseline, patients with acute TSCI had higher serum sclerostin concentrations. Studies consistently show sclerostin concentrations are highest in the acute phase and correlate with shorter time since injury during the first 5-years [25, 31]. Sclerostin elevations likely reflect dysregulated osteoblastic signalling pathways after acute skeletal unloading. Sclerostin (encoded by SOST gene) is an osteocyte-derived inhibitor of Wnt signalling and hence diminishes bone formation [32]. Osteocytes respond to skeletal loading-induced mechanical strain by downregulating sclerostin expression and triggering increased bone formation (mechanotransduction) [32]. The importance of sclerostin to skeletal homeostasis is well-established, and romosozumab (anti-sclerostin monoclonal antibody) has emerged as a potent osteoanabolic agent in osteoporosis treatment [32, 33]. In chronic TSCI, sclerostin concentrations correlate with knee and hip BMD rather than time since injury and hence lower sclerostin levels may reflect increasing osteoporosis severity [31, 34, 35]. No studies have explored longitudinal changes in sclerostin concentrations post-TSCI, and hence the timing of sclerostin peak is unclear. Data are also lacking for whether circulating sclerostin concentrations reflect osseous sclerostin expression. De Mare et al. showed serum sclerostin moderately correlated with osseous sclerostin expression in patients with end-stage renal failure (n = 68) [36]. However, sclerostin concentrations (including with the DiaSorin assay) are elevated in renal impairment (unpublished data) which may have impacted these results. There is emerging interest in the use of romosozumab for post-TSCI bone loss, with studies in acute (NCT04597931) and chronic SCI (NCT05101018, NCT04232657) recruiting.

At baseline, chronic TSCI patients had lower BMD in femoral neck and total hip with between-group differences more pronounced for distal femur and proximal tibia BMD, whilst lumbar spine BMD was relatively spared. Lower BMD values in the proximal femur, distal femur and proximal tibia all correlated with longer time since injury. These results are consistent with other studies comparing BMD between acute and chronic SCI cohorts. Duration since injury is an established risk factor for BMD loss after SCI, as patients have more prolonged exposure to sub-lesional bone loss [4, 6, 23, 25].

Acute phase reactions (APRs) occurred in all but two patients in our cohort of acute TSCI patients receiving ZOL (9/11; 82%) despite prophylactic paracetamol [38] although no cases were severe or prolonged. APRs occur commonly in ~ 40% of postmenopausal women with osteoporosis receiving their first dose of ZOL [17]. The high rate of APRs in our acute TSCI cohort are consistent with other such studies (pooled incidence 69% (55/80)), albeit APRs being heterogeneously defined [24, 26, 28, 29, 37] (Supp. Table 2). The underlying mechanism for seemingly high rates of APR after acute TSCI has not been elucidated. In our cohort, given almost all patients had an APR (all grade II), we were unable to examine risk factors for presence and severity of APR. Exaggerated bone turnover in acute TSCI may play a role. Higher concentrations of bone turnover markers (P1NP, CTx), although only modestly, have been associated with increased APR risk in cohorts of predominantly postmenopausal women [39, 40]. The acute inflammatory state of TSCI may also contribute, given the immune mechanism for APR and association with higher inflammatory markers [41, 42]. However, inflammatory markers have not routinely been assessed in acute TSCI patients receiving ZOL. Acute TSCI cohorts are typically young and although younger age was shown to be a risk factor in postmenopausal osteoporosis, this was in the range of early-60's to late-70's [17, 39]. Patients with acute TSCI typically are male, with higher BMD at time of injury and no prior oral bisphosphonate exposure, and it is unclear whether these may further contribute to increased APR risk [17, 39,40,41, 43].

Despite early ZOL in our acute TSCI cohort, rapid BMD loss still occurred at the hip and particularly at the knee. Conclusions regarding efficacy of ZOL in preventing BMD loss are however limited in the absence of controls with acute TSCI not receiving ZOL. However, given patients still lost a mean 15% BMD in the hip and 20% in the knee over 4-years, it is unlikely any benefit of ZOL was clinically meaningful in preventing BMD loss. Our results are consistent with prior small prospective controlled trials which utilised a single infusion of ZOL in the first 3–4-months post-TSCI with majority of studies limited to 1-year follow-up [24, 26,27,28,29, 37, 44] (Supp. Table 2). Participants experienced some attenuation of hip BMD (net difference of ~ 10–15% vs controls) one year after ZOL, however, still lost ~ 5–10% of BMD, suggesting more effective strategies are needed to completely attenuate bone loss. A second annual infusion of ZOL was utilised in an exploratory extension of one study which completely attenuated BMD loss at the total hip and femoral neck, and thus a strategy of two annual infusions of ZOL early in acute TSCI warrants further investigation.

At time of study conceptualisation, only two studies had reported knee BMD outcomes after ZOL in acute TSCI with disappointing results (Supp. Table 2). Bauman et al. assessed thirteen patients with acute TSCI managed with (n = 6) and without (n = 7) early ZOL [37]. The treatment group experienced significantly greater BMD losses compared to controls at the distal femur and proximal tibia after 12 months, unexplained by low precision. However, the controls in this study, despite all having motor-complete TSCI, had far less pronounced knee BMD losses than expected in the first year post-TSCI. Schnitzer et al. conducted a randomised placebo-controlled trial in seventeen patients with acute TSCI [28]. A single infusion of ZOL led to 5–10% better knee BMD responses at 6 months, however patients still experienced mean total BMD loss > 20% at the knee after 2-years. A recent study supported the early but short-lasting effect of ZOL on preventing knee BMD loss, with a difference of 6–8% at 4 months favouring ZOL but minimal-to-no difference by 12 months [27]. A larger placebo-controlled study (n = 60) utilised CT-derived BMD assessment of the distal femur and proximal tibia and similarly showed partial attenuation of cortical and trabecular BMD losses at 12 months but dramatic BMD losses in both groups at 24 months [26]. Collectively, these studies suggest a single infusion of ZOL may help prevent some bone loss at the knee in the first 6 months post-TSCI, but that the benefit is almost all lost as early as 2-years. Unlike with hip BMD, two annual ZOL infusions were unable to prevent dramatic declines in CT-derived compartmental knee BMD [25]. Given the importance of knee BMD assessment in TSCI, we developed an institutional protocol for this measurement which demonstrated a good degree of precision. Our study is the first to report BMD outcomes beyond 2 years in patients receiving ZOL in acute TSCI and demonstrated ongoing rapid bone loss around the knee in the 3rd and 4th years post-injury at a similar rate to that seen in the first 2 years. Our results, despite absence of a control group, are consistent with previous studies demonstrating lack of meaningful knee BMD response to a single ZOL infusion and indicate other treatment approaches need to be investigated. The use of short-term 6-monthly denosumab has been shown to prevent early hip and knee BMD loss in acute TSCI. However ~ 10–15% BMD losses occurred within 12 months of subsequent denosumab cessation, and hence this may not be a suitable strategy particularly given the younger age of acute TSCI cohorts [45].

In prior studies evaluating ZOL for preventing acute bone loss after TSCI, there was no delineation regarding clinical or pathological factors which may predict a better (or worse) BMD response. Complete motor impairment below the lesion is a marker of lesional severity and is a consistent risk factor for greater bone loss and fracture risk post-TSCI [3, 9, 10]. Despite this, our study is the first to perform an analysis comparing BMD responses to ZOL according to lesional severity. Our data suggests patients with motor-complete lesions tend to have greater BMD losses in the proximal tibia and distal femur after early ZOL. Patients with motor-complete lesions may represent a ‘high-risk’ cohort who require more intensive early pharmacotherapy to prevent acute bone loss. Despite a seemingly large numerical difference, this result is hypothesis-generating only and warrants further exploration in larger longitudinal studies.

Our study possesses various limitations. There was no direct control group for the acute interventional TSCI cohort as despite the non-interventional cohort not receiving ZOL, these patients were recruited much later after their injury. Given there had been some placebo-controlled evidence published prior to study conceptualisation that a single infusion of ZOL can attenuate some BMD loss at the hip in acute TSCI, we deemed it unethical to randomise our cohort to receive placebo, particularly given this study aimed to assess outcomes over a longer four year period. In our study, a cohort of patients with chronic TSCI were included to facilitate baseline comparisons in musculoskeletal parameters and also to assess the natural history of bone turnover and bone loss in this cohort. Adjunctive rehabilitation procedures were not recorded and ambulatory status of patients was not formally assessed, which would have allowed more detailed characterisation of our cohort. Participant recruitment was limited by constraints of the COVID-19 pandemic and geographical barriers as Royal North Shore Hospital is a tertiary referral centre for patients with TSCI including from regional and rural New South Wales. There were instances of missed BMD assessments (e.g., due to loss to follow-up, geographic limitations, and musculoskeletal discomfort) which further limited power in longitudinal and subgroup analyses (particularly in the chronic TSCI cohort). Several patients had exclusion of lumbar spine BMD for analysis due to spinal surgery post-TSCI, although this is a less relevant site in TSCI-related osteoporosis. The study is strengthened by protocolised and precise assessment of BMD at the knee which is lacking in several associated studies despite its demonstrated clinical relevance in TSCI-related osteoporosis. Comprehensive baseline clinical, biochemical and densitometric data allowed exploration of key musculoskeletal differences between acute and chronic TSCI patients. We were able to assess durability of response to a single infusion of ZOL in acute TSCI up to 4 years, with such an extended follow-up not previously reported.