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Annales d’Endocrinologie xxx (xxxx) xxx–xxx

Available online at

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www.sciencedirect.com

Original article

Bone mineral density progression following long-term simultaneous

pancreas-kidney transplantation in type-1 diabetes
Sílvia Santos Monteiro a,1,∗ , Tiago Silva Santos a,1 , Catarina A. Pereira a , Diana B. Duarte a ,
Filipa Silva b , La Salete Martins b , Jorge Dores a
a
Division of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário do Porto, Largo Professor Abel Salazar 4099-001 Porto, Portugal
b
Division of Nephrology and Transplant, Centro Hospitalar Universitário do Porto, Largo Professor Abel Salazar 4099-001 Porto, Portugal

a r t i c l e i n f o a b s t r a c t

Keywords: Introduction. – Simultaneous pancreas-kidney transplantation (SPKT) has demonstrated favorable impact
Bone mineral density on the progression of chronic complications in type-1 diabetes (T1D) and terminal chronic kidney disease
Osteoporosis (CKD). However, some CKD mineral and bone disorders (CKD-MBD) may persist, even after transplanta-
Simultaneous pancreas-kidney
tion. There are only a few studies addressing the long-term progression of bone mineral density (BMD)
transplantation
in these patients. Our aim was to assess baseline BMD and long-term progression and consequences in
Type 1 diabetes
patients with T1D undergoing SPKT.
Methods. – A retrospective cohort included patients undergoing SPKT in our tertiary center between
2000 and 2017. BMD progression was assessed on dual X-ray absorptiometry (DXA). Only patients with
baseline data and a minimum follow-up of 2 years were included.
Results. – Seventy-three patients were included, 53.4% male, with a median age at SPKT of 35 years
(interquartile range [IQR] 31; 39). At transplantation, the median T-scores for the lumbar spine (LS)
and femoral neck (FN) were −1.6 (IQR −2.6; −1.1) and -−2.1 (IQR −2.7; −1.6), respectively. Seventy-five
percent of patients presented low BMD (osteopenia or osteoporosis) in the LS and 90% in the FN, with 33%
osteoporosis in the LS and 36% in the FN. On multivariate analysis, male gender (odds ratio [OR] 10.82,
95% confidence interval (CI) 2.88–40.70) and low body-mass index (BMI) (OR 0.73, 95% CI 0.55–0.97)
were significantly associated with lumbar but not femoral osteoporosis. At long-term follow-up, BMD
significantly improved in the LS (T-score +0.41, P < 0.001) and FN (T-score +0.29, P = 0.01), at a median
4 years after SPKT. Twelve (16.4%) and 9 (12.3%) patients showed persistent FN and LS osteoporosis,
respectively. Multivariate linear regression showed that high BMI was predictive of improvement in
BMD.
Conclusions. – This study demonstrated severe skeletal fragility in T1D patients with terminal CKD under-
going SPKT, more than a quarter of whom showed osteoporosis. The significant improvement in BMD may
result from metabolic correction by SPKT and from physiological skeleton mineralization, which contin-
ues in this age group. BMD progression was positively associated with BMI, due to improved nutritional
balance after transplantation.
© 2023 Elsevier Masson SAS. All rights reserved.

1. Introduction kidney graft survival and either stabilization or improvement of

Simultaneous pancreas-kidney transplantation (SPKT) is the
optimal treatment in younger patients with type 1 diabetes (T1D)
and chronic kidney failure, while islet-after-kidney transplantation
is a safe alternative in older patients with severe macroangiopa-
thy, providing an euglycemic state usually associated with longer
∗ Corresponding author.
E-mail address: silviamsmonteiro@hotmail.com (S. Santos Monteiro).
1
Equal contribution.
diabetes-related complications such as diabetic retinopathy and
peripheral neuropathy [1].
However, chronic kidney disease mineral and bone disorder
(CKD-MBD) is a significant complication. The incidence of pre-
existing low-turnover bone disease in patients on hemodialysis has
been increasing, due to higher dialysate calcium concentrations,
high doses of calcium-containing phosphate binders and poten-
tially overzealous use of active vitamin D metabolites [2]. On the
other hand, diabetic renal disease and progression to renal fail-
ure are often associated with secondary hyperparathyroidism and
high bone turnover, which also results in bone loss [2]. Progressive

https://doi.org/10.1016/j.ando.2023.03.002
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Please cite this article as: Santos Monteiro S, et al, Bone mineral density progression following long-term simultaneous pancreas-kidney
transplantation in type-1
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S. Santos Monteiro et al.
decline in bone mineral density (BMD) and subsequent develop-
ment of osteopenia and osteoporosis are frequent [2]. Moreover,
the incidence of post-SPKT fracture is considerably higher than with
other solid organ transplants [3]. Several factors may contribute
to this poorer outcome: the severity of pre-existing CKD-MBD,
hypophosphatemia, pre-transplantation fibroblastic growth fac-
tor 23-parathyroid-vitamin D axis disorder, persistent parathyroid
disease, malabsorption related to pre-transplantation pancreatic
exocrine deficiency or celiac disease, degree of kidney function
recovery and the negative impact of immunosuppressive agents,
especially steroids [2,4,5]. Additionally, diabetic retinopathy and
neuropathy are risk factors for falls and consequent fragility frac-
tures. Effective preventive strategies to correct bone loss and
mineral abnormalities are essential but often insufficient [2].
The 2017 Kidney Disease: Improving Global Outcomes (KDIGO)
guidelines already recognized that BMD efficiently predicts fracture
risk in this population. The guidelines highlight the need to measure
BMD and distinguish between the immediate post-transplantation
period (within the first 3 months), with rapidly changing glomeru-
lar filtration rate (GFR), and the subsequent period when stable
graft function has been obtained [2].
Evidence addressing the long-term evolution of BMD after SPKT
is scarce. Therefore, our aim was to evaluate and characterize base-
line lumbar and femoral BMD and its long-term evolution and
consequences in patients with T1D undergoing SPKT.
2. Patients and methods
2.1. Patient selection and study design
We performed a retrospective longitudinal cohort analysis,
including individuals with T1D and chronic renal failure undergo-
ing SPKT in our tertiary center between May 2000 and December
2017. T1D diagnosis was based on undetectable C-peptide lev-
els (< 0.02 ng/mL) and positive pancreatic islet autoimmunity
(autoantibodies to glutamic acid decarboxylase, tyrosine phos-
phatase islet antigen 2 and/or zinc transporter 8). Grafts were
obtained from deceased donors (both grafts from the same
donor) using systemic-enteric drainage (venous drainage to the
iliac vein; exocrine drainage through an enteric anastomosis of
the pancreatic-duodenal arch). The immunosuppressive protocol
was constant throughout the study period, with anti-thymocyte
globulin, tacrolimus, mycophenolate mofetil and steroids. When-
ever possible, steroids were rapidly withdrawn and discontinued
at the end of the first year. Only patients with baseline pre-
transplantation BMD data and minimum post-transplantation
follow-up of 2 years were included. Data regarding gender, age at
transplantation, diabetes duration, body mass index (BMI), time on
dialysis, renal replacement technique, fragility fractures, biochem-
ical results and densitometric parameters were regularly recorded
during follow-up. We carefully evaluated and excluded other clin-
ically relevant causes of osteoporosis: celiac disease, rheumatoid
arthritis, and primary or tertiary hyperparathyroidism. Negative
serum tissue transglutaminase IgA antibodies ruled out celiac dis-
ease and the absence of increased parathyroid hormone (PTH)
levels in the setting of hypercalcemia ruled out primary or tertiary
hyperparathyroidism.
The study was approved by the local review board (250-
DEFI/267-CES). Consent to participate was waived due to the
retrospective nature of the study and full data anonymization.
2.2. Laboratory measurements
Pancreas graft function was determined by measuring fasting
glycemia, C-peptide and glycosylated hemoglobin (HbA1c). HbA1c
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Annales d’Endocrinologie xxx (xxxx) xxx–xxx
was assessed by high-performance liquid chromatography, cal-
ibrated on the International Federation of Clinical Chemistry and
Laboratory Medicine (IFCC) reference procedure [6]. Kidney graft
function was determined by measuring serum creatinine and esti-
mated GFR levels using the CKD-EPI formula [2]. Serum calcium,
phosphorus, albumin, 25-hydroxy vitamin D, creatinine, alkaline
phosphatase and osteocalcin were analyzed spectrophotometri-
cally using automated techniques. Serum calcium concentrations
were adjusted to an albumin concentration of 4 g/dL. Intact PTH
levels were measured by electrochemiluminescence immunoassay.
2.3. Bone densitometry
All patients underwent dual X-ray absorptiometry (DXA) of the
L1-L4 lumbar spine (LS), total hip (TH) and femoral neck (FN). BMD
was assessed on the same Hologic QDR® 4500 X-ray Bone Densit-
ometer throughout the study period. DXA scan quality control was
ensured by daily scanning of the spine phantom. The coefficients of
variation for FN and LS BMD measurements were 2% and 1%, respec-
tively. Changes in BMD () were calculated from the absolute BMD
values (g/cm2 ). Data were expressed as gender-specific T-scores
(standard deviation from the mean BMD for a young healthy pop-
ulation). Osteoporosis was defined as a T-score of −2.5 or lower
and osteopenia as a T-score between −1.0 and −2.5, according to
World Health Organization guidelines [7]. Z-score data (standard
deviation from the mean BMD for a population of the same age)
were not available for inclusion in the analysis.
2.4. Statistical analysis
Statistical analysis used the IBM SPSS® computer statistics
program, version 25.0. For continuous quantitative variables, distri-
bution normality assessed was on histogram and Shapiro-Wilk test.
Results were presented as median (interquartile range [IQR]) due
to the non-normal distribution of most variables. Categorical vari-
ables were expressed as percentages and ratios. The Mann-Whitney
test for continuous variables and Pearson’s chi-square test for cate-
gorical variables were used to analyze differences between groups.
For significant factors on univariate analysis, multivariate logistic
regression models were created by stepwise-forward elimination
of non-significant factors. The Wilcoxon signed rank was used
to analyze differences at follow-up. A stepwise multivariate lin-
ear regression model with BMD as dependent variable identified
clinical predictors of change in bone density ( BMD). Potential
contributing factors were selected based on the literature and bio-
logical plausibility. All statistical tests were two-tailed, with P < 0.05
considered statistically significant.
3. Results
Two hundred and eleven patients underwent SPKT between
May 2000 and December 2017 (280 months): 50.2% female; median
age at transplantation, 35 years (IQR 30; 39); median time since
diabetes diagnosis, 23 years (IQR 18; 27); and median time on
dialysis, 22 months (IQR 12; 32). The inclusion criteria selected
73 patients: 53.4% male; median age at transplantation, 35 years
(IQR 31; 39); median diabetes duration, 24 years (IQR 19; 28);
and median time on dialysis, 22 months (IQR 12; 30). Fifty-
five (89%) presented undetectable C-peptide levels (< 0.02 ng/mL),
while 56 (77%) had positive pancreatic islet autoantibodies (glu-
tamic acid decarboxylase, tyrosine phosphatase islet antigen 2
and/or zinc transporter 8). All presented negative levels of serum
tissue transglutaminase IgA antibodies. All the women (n = 34) were
premenopausal, 21 of whom (62%) were on oral contraceptives: 16
(47%) with estroprogestatives and 5 (15%) with progestins. Median
PTH levels were elevated (197 pg/mL: reference range 15–65)
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Table 1 0.00; 0.80; P = 0.01). Fig. 2 shows the evolution of BMD in the LS
Baseline demographic and clinical characteristics of SPKT recipients at time of
and FN during follow-up. There was a positive correlation between
transplantation.
BMI and BMD in the LS (r = 0.34, P = 0.01) and FN (r = 0.38, P = 0.004).
SPKT recipient characteristics n = 73 Twelve (16.4%) and 9 (12.3%) patients showed persistent osteo-
Male 53.2% (n = 39) porosis in the femoral and lumbar regions, respectively. There were
Age at transplantation (years) 35 (31–39) no fragility fractures during follow-up. On the linear regression
BMI (kg/m2 ) 21.6 (20.5–23.5) model adjusted for age, gender, duration of diabetes, BMI and
Diabetes duration (years) 24 (19–28)
cumulative glucocorticoid dose, higher BMI values were associated
HbA1c (%) 8.2 (7.4–9.5)
Time on dialysis (months) 22 (12–30) with significant improvement in BMD: each 10% increase in BMI
Renal replacement technique led to a 3.8% and 3.5% increase in BMD in the FN (ˇ = 3.7646,
Hemodialysis 69% (n = 50) P = 0.04) and LS (ˇ = 3.46, P = 0.08), respectively.
Peritoneal dialysis 27% (n = 20)
During follow-up, 55 (75%) and 24 (33%) individuals received at
None 4% (n = 3)
Calcium (2.10–2.45 mmol/L) 2.17 (2.02–2.28) least 400IU vitamin D and 1000 mg elemental calcium, respectively.
Phosphorus (0.87–1.45 mmol/L) 1.25 (0.88–1.58) Twenty (27%) were under oral or intravenous bisphosphonate anti-
Parathyroid hormone (15–65 pg/mL) 197 [117–345] osteoporotic drug therapy. There were no significant differences
25-hydroxy vitamin D (> 50nmol/L) 20 (8–38) between individuals with or without treatment with bone-active
Alkaline phosphatase (32–104U/L) 54 (39–82)
drugs in BMD or prevalence of osteoporosis or fracture, in the
Osteocalcin (11–46 ng/mL) 213 (74–269)
Lumbar T-score −1.6 (−2.6; −1.1) FN or LS. All women remained premenopausal, 14 of whom (41%)
Femoral T-score −2.1 (−2.7; −1.6) were on estroprogestatives and 5 (15%) on progestins. No patients
BMI: body mass index; HbA1c: glycosylated hemoglobin; SPKT: simultaneous received pancreatic extract treatment during follow-up.
pancreas-kidney transplantation. Results are shown as median (interquartile range)
or number (percentage).
4. Discussion

and median 25-hydroxy vitamin D levels were low (20nmol/L:
reference range > 50nmol/L). No patients were under vitamin D
supplementation before transplantation. Median LS and FN T-
scores were −1.6 (IQR −2.6; −1.1) and −2.1 (IQR −2.7; −1.6),
respectively. Pre-transplant baseline characteristics are summa-
rized in Table 1.
Fifty-five (75%) patients had low bone mass (either osteopenia
or osteoporosis) in the LS and 66 (90%) in the FN, and 24 (33%)
and 26 (36%) respectively had osteoporosis (Fig. 1). On univariate
analysis, low BMI and male gender were associated with LS but not
FN osteoporosis. No associations were found between basal BMD
and time on dialysis, diabetes duration, HbA1c, calcium/phosphate,
25-hydroxy vitamin D, PTH or bone turnover markers (Table 2). On
multivariate analysis, male gender (OR 10.82, 95% CI 2.88–40.70)
and low BMI (OR 0.73, 95% CI 0.55–0.97) significantly increased the
risk of LS osteoporosis.
3.1. Long-term follow-up
Median follow-up was 4 years (IQR 2; 6), during which 6 (8%) and
3 (4%) patients lost their functioning pancreatic and kidney grafts,
respectively, all within the first post-transplantation year. Exclud-
ing these patients from the analysis did not change our results.
All others remained insulin-independent with stable renal func-
tion. Cumulative prednisolone dose was similar in most patients, as
glucocorticoid tapering was initiated within the first 6 months post-
transplantation with complete withdrawal at the end of the first
year, except for 8 individuals (11%) who remained under glucocor-
ticoids at a minimal dose of 5 mg prednisolone at end of follow-up.
PTH and serum phosphate levels significantly decreased during the
first post-transplantation year, and both remained stable over long-
term follow-up. Serum calcium and 25-hydroxy vitamin D levels
increased during the same period, but only calcium levels signif-
icantly increased during the remaining follow-up period. When
available, alkaline phosphatase and osteocalcin levels did not show
significant change after SPKT (Table 3).
In the first post-transplantation year, BMD significantly
decreased in the LS (median T-score −0.40; IQR −0.60; 0.10;
P < 0.001), but remained stable in the FN (median T-score −0.05;
IQR −0.15; 0.10; p = 0.15). During long-term follow-up, BMD grad-
ually and significantly improved in the LS (median T-score +0.41;
IQR −0.20; 0.60; P < 0.001) and FN (median T-score +0.29; IQR
This single-center cohort study evaluated and characterized
bone metabolism parameters in individuals with T1D and terminal
chronic renal failure who had undergone SPKT. At transplantation,
75% of subjects presented low bone mass (90% in the femoral neck),
while around 35% were in the osteoporotic range. Indeed, despite
their relatively young age (median, 35 years), only 10% had nor-
mal BMD values at all major sites. Our results are concordant with
previously published studies of SPKT, which also reported a high
incidence of osteoporosis at transplantation (27–37%) [8–10]. Cor-
tical osteoporosis and osteopenia were more prevalent, probably
because T1D is an independent risk factor for low bone mass, con-
sidering both the baseline insulin-deficient state and the effect of
advanced glycated end products in the bone metabolism [11]. In
addition, T1D frequently presents features of pancreatic exocrine
insufficiency, and some degree of malabsorption may lead to min-
eral abnormalities and reduce BMD.
Contrary to our expectations, male gender was a risk factor for
LS osteoporosis at transplantation, even after adjustment for age,
BMI, diabetes duration and HbA1c. Other studies reported similar
findings, showing a higher prevalence of lumbar osteoporosis in rel-
atively young men than in healthy control adults, or even than in
women with T1D and chronic renal failure [10,12,13]. The underly-
ing pathophysiological mechanisms are unknown, but these results
confirm that T1D has a major effect on bone turnover. In addition,
men with T1D frequently present some level of hypogonadism,
commonly exacerbated by development of chronic renal disease,
which, although not systematically evaluated in our cohort, may
partially explain our results [14,15].
BMI was an important determinant of skeletal status, and low
baseline BMI was a risk factor for LS osteoporosis, including on
multivariate analysis. This association between low BMD and low
BMI was previously reported in kidney transplant recipients, and
several mechanisms are presumed to contribute: conversion of
androgen to estrogen in the adipose tissue, and adipokine action
in bone remodeling [16,17]. At long-term follow-up, a clinical mul-
tivariate linear model found that the only clinical predictor of
improvement in BMD was high BMI.
There was a high rate of vitamin D deficiency at baseline, con-
sistent with previous studies in T1D and chronic kidney failure
[18,19]. Despite their intrinsically increased risk of skeletal fragility,
patients were not under pre-transplantation vitamin D supplemen-
tation. Low 25-hydroxy vitamin D levels have been associated with

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Fig. 1. Osteopenia and osteoporosis in SKPT recipients at transplantation. A. Lumbar spine. B. Femoral neck.

Table 2
Risk factors for lumbar spine and femoral neck osteoporosis on univariate analysis.

SPKT recipient Osteoporotic lumbar spine Osteoporotic femoral neck

characteristics
Yes (n = 24) No (n = 49) P Yes (n = 26) No (n = 47) P

Male (%) 20 (83) 19 (39) < 0.001 13 (50) 26 (55) 0.81

Age at transplantation 35 (31–39) 35 (32–40) 0.43 36 (32–41) 35 (31–39) 0.36
(years)
BMI (kg/m2 ) 20.9 22.3 0.03 21.3 22.0 0.19
(20.2–22.0) (20.6–23.8) (22.2–22.9) (20.6–22.8)
Diabetes duration 22 (21–26) 25 (19–28) 0.81 24 (21–27) 25 (19–28) 0.25
(years)
HbA1c (%) 8.4 (8.0–9.9) 8.1 (7.2–9.1) 0.07 8.2 (7.6–9.9) 8.2 (7.4–9.1) 0.32
Time on dialysis 24 (12–30) 21 (13–31) 0.81 26 (14–32) 20 (11–30) 0.26
(months)
eGFR (mL/min/1.73m2 ) 64 (53–75) 62 (51–77) 0.99 65 (56–74) 65 (55–73) 0.96
Calcium 2.18 2.16 0.39 2.20 2.14 0.38
(2.10–2.45 mmol/L) (2.08–2.28) (2.00–2.28) (2.06–2.28) (2.01–2.29)
Phosphorus 1.39 1.22 0.16 1.40 1.20 0.34
(0.87–1.45 mmol/L) (1.09–1.64) (0.82–1.51) (0.85–1.61) (0.92–1.44)
Parathyroid hormone 161 (115–341) 207 (122–339) 0.57 194 (120–334) 200 (112–345) 0.91
(15–65 pg/mL)
25-hydroxy vitamin D 22 (18–45) 11 (8–31) 0.19 20 (8–52) 20 (8–31) 0.93
(> 50nmol/L)
Alkaline phosphatase 54 (42–64) 66 (38–89) 0.91 55 (26–103) 54 (42–70) 0.95
(35–104U/L)
Osteocalcin 209 (90–246) 236 (78–271) 0.80 213 (74–256) 219 (78–272) 0.72
(11–46 ng/mL)
Lumbar T-score −2.8 (−3.0; −1.2 (−1.6; < 0.001 −2.6 (−2.8; −1.3 (−0.8; 0.003
−2.6) −0.6) −1.6) −2.2)
Femoral T-score −2.6 (−3.1; −1.8 (−2.3; < 0.001 −3.0 (−3.2; −1.8 (−1.5; < 0.001
−2.1) −1.5) −2.6) −2.1)

BMI: body mass index; eGFR: estimated glomerular filtration rate; HbA1c: glycosylated hemoglobin; SPKT: simultaneous pancreas-kidney transplantation. Results are shown
as median (interquartile range) or number (percentage). Bold values represent statistical significance (P < 0.05).

secondary hyperparathyroidism and high bone turnover markers,
and consequently with decreased BMD [2]. However, our results
did not demonstrate any significant relationship between baseline
25-hydroxy vitamin D levels and BMD.
Two main factors are known to adversely influence BMD in
the first year after transplantation: glucocorticoids and hyper-
parathyroidism. Our data showed significant bone loss during
this period only in the lumbar spine, which is probably related
to glucocorticoid therapy, especially with high immediate post-
transplantation dosage, increasing bone loss in trabecular sites [20].
Steroids can increase bone loss by several mechanisms, such as
increased osteoclastic activity or a “toxic” effect on osteoblasts [21].
There was progressive improvement in BMD after the first year,
which was more pronounced in the trabecular lumbar spine than
the femoral neck, consistent with previous studies [8,9,22]. Gluco-
corticoid withdrawal in the long term was achieved in about 90%
of patients, and further contributed to improving long-term BMD.
Other immunosuppressive agents seem to be irrelevant [21]. On
the other hand, in patients with secondary hyperparathyroidism,
PTH secretion normalized early in the post-transplantation period,
leading to further normalization of bone remodeling and increas-
ing long-term BMD. These results for stabilization of BMD after the
first post-transplantation year are consistent with other studies of
SPKT recipients [8,9]. It may result both from correction of pre-SKPT
metabolic disorder and from physiological mineral capitalization of
the skeleton that continues in these age groups. Additionally, BMD
progression was positively associated with BMI, due to improved
nutritional balance with transplantation and restoration of eug-
lycemia, avoiding glycosuria.
Treatment strategies to prevent and reverse bone loss include
adequate nutrition, adapted anti-gravity physical activity, and
calcium carbonate, vitamin D analogs and bisphosphonates, if nec-
essary. Some of our patients were treated with these drugs during
follow-up, which may have contributed to a significant increase
in BMD. Probably, our sample size was insufficiently powered to
reveal differences in outcome between patients with or without

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Table 3
Clinical and laboratory data during follow-up.

SPKT recipient characteristics At SPKT 1-year post-SPKT Long-term

BMI (kg/m2 ) 21.6 (20.5–23.5) 21.7 (20.1–24.0) 22.0 (19.8–24.1)

eGFR (mL/min/1.73m2 ) 70 (47–84) 67 (50–81) 69 (49–82)
Prednisolone 100% 38%a 11%a,b
HbA1c (%) 8.2 (7.4–9.5) 5.3 (5.0–5.7)a 5.5 (5.2–5.9)a
C-peptide (1.10–4.40 ng/mL) 4.6 (2.4–7.2) 2.20 (1.78–3.19)a 2.46 (1.85–2.89)a
Calcium (2.10–2.45 mmol/L) 2.17 (2.02–2.28) 2.41 (2.32–2.50)a 2.45 (2.37–2.52)a,b
Phosphorus (0.87–1.45 mmol/L) 1.25 (0.88–1.58) 1.04 (0.91–1.19)a 1.04 (0.94–1.13)a
Parathyroid hormone 197 (117–345) 62 (47–88)a 62 (46–84)a
(15–65 pg/mL)
25-hydroxy vitamin D 20 (8–38) 58 (40–107)a 75 (38–106)a
(> 50 nmol/L)
Alkaline phosphatase 54 (39–82) NA 43 (31–49)
(35–104U/L)
Osteocalcin (11–46 ng/mL) 213 (74–269) NA 120 (18–310)
Lumbar T-score −1.60 (−2.60; −1.10) −2.00 (−2.72; −1.20)a −1.20 (−2.00; −0.70)a,b
Femoral T-score −2.10 (−2.70; −1.60) −2.15 (−2.62; −1.70) −1.90 (−2.30; −1.40)a,b

BMI: body mass index; eGFR: estimated glomerular filtration rate; HbA1c: glycosylated hemoglobin; SPKT: simultaneous pancreas-kidney transplantation. Results are
shown as median (interquartile range) or percentage. NA: non-applicable due to missing data. Median follow-up of 4 (IQR 2–6) years. All data collected within a 3-month
pre-transplantation period were considered “At SPKT”.
a
P < 0.05 versus “At SPKT” evaluation.
b
P < 0.05 versus “1-year post-SKPT” evaluation.

Fig. 2. Progression of bone mineral density in lumbar spine (LS) and femoral neck (FN) during follow-up.

bone-active medication. Moreover, data on these medications in
solid organ transplantation are still scarce, and benefit for SPKT
recipients remains to be proven [21]. Larger controlled randomized
clinical trials are unwarranted to fully assess their impact within
this specific population.
This study had some limitations. Firstly, its retrospec-
tive design raises the issue of selection and information
bias. Data for nutritional status, hypothalamic-pituitary-
gonadal axis status, calcium-phosphate metabolism, bone
turnover markers and fractures during long-term follow-up
were missing in some patients, which may have affected
our results. Considering the median age at transplantation
(35 years), Z-score would have been the standard param-
eter to accurately calculate BMD, but was not available in
most cases. However, we carefully evaluated and excluded
other clinically relevant causes of osteoporosis. Secondly, we
were not able to evaluate BMD during the first 6 months
post-transplantation, a critical period for treatment and pre-
vention of bone loss. Thirdly, the efficacy of anti-osteoporosis
drugs could not be assessed, due to lack of power. Lastly, we
must not forget that “precise” diagnosis of CKD-MBD can only be
established by biopsy, which alone can accurately differentiate
between standard osteoporosis and all the other subtypes of bone
disease in CKD patients.
A strong point of the study was is that it is one of the largest
cohorts published to assess BMD in SPKT recipients, in both
the short- (first year) and long-term post-transplantation period.
Moreover, the long follow-up allowed us to evaluate BMD longi-
tudinally and associate BMI gain with BMD improvement in the
long term. In addition, all patients underwent standardized pre-
and post-transplant care, including a steroid-sparing immuno-
suppressive protocol, which increased sample homogeneity and

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G Model
ANDO-1487; No. of Pages 6 ARTICLE IN PRESS
S. Santos Monteiro et al.
strengthened statistical comparisons. Lastly, given that published
studies on this subject are scarce and inconsistent, we consider that
our study adds valuable data [8–11].
5. Conclusion
The present study demonstrated considerable skeletal fragility
in patients undergoing SPKT, more than a quarter of whom showed
criteria for osteoporosis. The significant improvement in BMD may
result from metabolic correction by SPKT and physiological min-
eral capitalization of the skeleton, which continues in this age
group. BMD progression was positively associated with BMI, due to
improved nutritional balance with transplantation and restoration
of euglycemia, avoiding glycosuria.
Disclosure of Interest
The authors declare that they have no competing interest.
Funding information
This research did not receive any specific grant from any funding
agency in the public, commercial or not-for-profit sector.
Author contributions
Sílvia Santos Monteiro: conceptualization; methodology; inves-
tigation; formal analysis; writing – original draft – review & editing.
Tiago Silva Santos: conceptualization; methodology; investiga-
tion; formal analysis; writing – original draft – review & editing.
Catarina Alves Pereira: investigation; writing – review & editing.
Diana Borges Duarte: investigation; writing – review & editing.
Filipa Silva: investigation; writing – review & editing.
La Salete Martins: investigation; writing – review & editing.
Jorge Dores: conceptualization; methodology; investigation;
writing – review & editing.
All authors approved the final version submitted and are
accountable for all aspects of the work. All authors read and
approved the final manuscript.
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