CHRONIC KIDNEY DISEASE
Renal bone disease
Thomas Phillips
Cathy Pogson
Kristin Veighey
John Cunningham
Abstract
Sustained loss of kidney function leads to the evolution of progressive sec-
ondary hyperparathyroidism associated with a characteristic high-turnover
form of metabolic bone disease. The drivers of hyperparathyroidism
include the failure of renal bioactivation of vitamin D, phosphate retention
and, in some cases, hypocalcaemia. As renal impairment becomes more
severe, some patients, particularly under the influence of treatment, and
particularly if they have diabetes, evolve in a different direction; here,
low-turnover adynamic bone disease develops, associated with relative
suppression of the parathyroid glands. Uraemic patients also develop an
internal milieu that favours soft tissue calcification involving the peri-
articular tissue, skin and vasculature. Arterial calcification is closely associ-
ated with arterial stiffening, left ventricular disease and increased cardio-
vascular morbidity and mortality. Current therapies aim to minimize
disturbances of skeletal integrity by maintaining calcium, phosphate,
vitamin D and parathyroid hormone concentrations within defined target
ranges. It is hoped, but not yet established, that these measures will also
result in a reduction of cardiovascular events in this vulnerable population.
Keywords Calcimimetics; chronic kidney disease; chronic kidney
disease mineral and bone disorder; hyperparathyroidism; vascular
calcification; vitamin D
Introduction
The onset of a significant and sustained reduction in renal function
is invariably associated with the development of metabolic bone
disease, disturbances in the metabolism of calcium and phos-
phorus, and abnormalities of the principal calcium-regulating
hormones calcitriol, parathyroid hormone (PTH) and fibroblast
growth factor 23 (FGF-23, a potent phosphaturic hormone secreted
by osteocytes). There are also important links between these dis-
turbances of mineral metabolism and adverse cardiovascular
Thomas Phillips MB BS BSc MRCP(Neph) is a Renal Registrar and Research
Fellow with an interest in chronic kidney disease at University Hospital
Southampton, UK. Competing interests: none declared.
Cathy Pogson BPharm MRPharmS DipClinPharm NMP is a Specialist Renal
Pharmacist at Wessex Kidney Centre, Portsmouth Hospitals
University NHS Trust, UK. Competing interests: CP has received fees
from Astellas.
Kristin Veighey MRCP(Neph) PhD is a NIHR Academic Clinical Fellow in
General Practice and a Renal Consultant. She completed her renal training
in London and Portsmouth. Competing interests: none declared.
John Cunningham DM FRCP is a Professor of Nephrology at The
Royal Free Hospital and University College London, UK and an active
researcher and clinician. Competing interests: none declared.
MEDICINE 51:3
Key points
C Hyperparathyroidism develops early in chronic kidney disease
(CKD), so should be treated early e if parathyroid hormone
(PTH) concentrations are elevated and rising, check the cal-
cium, phosphate and 25-hydroxyvitamin D concentrations and
treat accordingly
C Fibroblast growth factor 23 (FGF-23) increases as an early
adaptive mechanism against hyperphosphataemia in CKD
C There are important links between metabolic bone disease
and cardiovascular disease in CKD patients, so when treating
the bones, keep an eye on cardiovascular issues too
C Uraemic bone disease is heterogeneous; high-turnover
hyperparathyroid bone disease and low-turnover adynamic
bone disease dominate the two ends of the spectrum
C PTH measurement is a reasonable surrogate for the severity
and type of bone disease but is part of a greater constellation
of biomarkers that may in future help to differentiate different
bone turnover states
outcomes in patients with chronic kidney disease (CKD), collec-
tively termed CKD mineral and bone disorder (CKD-MBD).
Hyperparathyroidism and high-turnover bone disease
A reduction of renal cell mass and glomerular filtration rate
(GFR) leads to progressive phosphate retention and a failure of
renal bioactivation of vitamin D. These abnormalities stimulate
the parathyroid glands to synthesize and release increased
amounts of PTH, causing secondary hyperparathyroidism, and to
increase proliferative activity (Figure 1).
Failure of vitamin D bioactivation leads to a lower extracel-
lular fluid calcium concentration, providing further stimulus to
the parathyroid glands. Calcitriol (1,25-dihydroxycolecalciferol)
has a direct inhibitory effect on PTH gene transcription, medi-
ating its effects via a nuclear vitamin D receptor that is present in
the parathyroid glands, osteoblasts and intestinal epithelial cells,
and many other tissues. The parathyroid glands also express the
calcium-sensing receptor, a G-protein-coupled receptor that me-
diates rapid minute-to-minute responses to changes in extracel-
lular calcium ion concentration.1
At the level of bone, PTH at physiological or just supra-
physiological concentrations is anabolic. In contrast, sustained
elevation of PTH is catabolic, increasing the activity of both os-
teoblasts and osteoclasts, accelerating bone turnover and ulti-
mately leading to significant resorptive damage.
Key biomarkers in CKD-MBD
Elevated FGF-23 is associated with both the progression of kid-
ney disease and mortality; it rises early in CKD, preceding rises in
serum phosphate and PTH. Elevation of PTH and FGF-23 are
adaptive mechanisms but are under different feedback controls.
184 Ó 2022 Published by Elsevier Ltd.
 CHRONIC KIDNEY DISEASE
Figure 1
PTH is upregulated in response to decreases in serum calcium
and calcitriol concentrations, and increases in serum phosphate
concentration, all of which are partially or completely corrected
by the PTH increment. In contrast, FGF-23 release is upregulated
by increases in serum phosphate, so augments, and can even
dominate, the hormone-driven phosphaturic response to
decreasing GFR. Finally, FGF-23 powerfully downregulates the
renal production of calcitriol, thereby opposing the action of PTH
on the vitamin D endocrine system.
Phosphate independently correlates with mortality in patients
with end-stage renal failure on renal replacement therapy.
Because of its role in driving CKD-MBD, it has long been the
obvious therapeutic target.
The novel biomarkers sclerostin (a marker of bone formation)
and tartrate-resistant acid phosphatase-5b (TRAP-5b; a marker of
bone resorption produced by osteoclasts) are raised in CKD pa-
tients with bone fractures compared with those without. They
can therefore be useful biomarkers or, in the case of sclerostin,
even as a potential therapeutic target.
Extraskeletal calcification
Soft tissue calcification, especially involving large arteries, is a
frequent complication in individuals with CKD (Figure 2). This
calcification occurs in the vascular media and is distinct from the
intimal calcification seen in patients with atheromatous disease.
Medial calcification in uraemia is closely associated with loss of
MEDICINE 51:3
Figure 2 An unenhanced CT scan of the knee of a dialysis patient (in
the context of a new fracture) showing osteopenia and severe arterial
calcification (arrow).
vascular compliance, arterial stiffening and increased pulse-wave
velocity. These abnormalities increase ventricular afterload and
may be important in the genesis of uraemic cardiac disease and
the high cardiovascular mortality seen in these patients.
Assessment of osteodystrophy e bone pathology
associated with CKD
The typical derangement seen in a biochemical snapshot of un-
treated patients with advanced CKD shows high phosphate and
low calcium concentrations with resulting secondary hyper-
parathyroidism. If measured, calcitriol is invariably low and FGF-
23 very high. Skeletal X-rays are frequently normal, except in
cases of severe hyperparathyroidism, in which subperiosteal
erosion and cortical tunnelling may be seen.
More recent evaluations show that dual-energy X-ray absorp-
tiometry (DXA) testing in patients with CKD is helpful in
measuring bone mineral density (BMD) and therefore predicting
fracture risk. The Fracture Risk Assessment Tool (FRAX) has been
used to predict osteoporotic fractures in patients with CKD. Novel
radiological tests such as 18fluorine-labelled sodium fluoride
positron emission tomography computed tomography (CT) raise
the possibility of non-invasive testing of bone turnover state.
Adynamic bone disease
In some individuals, particularly those treated with active
vitamin D metabolites and with high exposure to calcium derived
from the diet or dialysate fluids, there is relative suppression of
185 Ó 2022 Published by Elsevier Ltd.
 CHRONIC KIDNEY DISEASE
PTH, with the result that the skeleton lacks a stimulatory
anabolic input. Abnormally low bone turnover develops, with
low cellular activity. This is associated with increased skeletal
morbidity and an associated increase in the tendency to develop
vascular calcification, with increased cardiovascular morbidity
and mortality. The risk of low-turnover bone disease increases
progressively with the severity of CKD, and in some studies has
been the dominant bone lesion identified in CKD stage 5 patients
on dialysis. For this reason, most guidelines have recommended
supraphysiological target ranges for PTH in dialysis patients.
Another contributor to low turnover is the use of anti-
resorptive agents such as bisphosphonates for the treatment of
osteoporosis. These agents reduce osteoclastic activity, but bone
metabolism remains coupled so new bone formation is also
reduced. Bisphosphonates are excreted by the kidney and
therefore accumulate in individuals with CKD. These drugs
should be viewed with caution when the estimated GFR (eGFR)
is <30 ml/minute/1.73 m2.
Some older biomarkers for bone turnover such as bone-specific
alkaline phosphatase are being reconsidered as potential flags for
low bone turnover states. Newer biomarkers such as WNT-b-cat-
enin correlate with increased bone turnover. A definitive diagnosis
of adynamic bone disease in CKD-MBD is via bone biopsy; however,
this is seldom undertaken because of the widespread lack of
expertise in the procedure and its histological interpretation. Inter-
national guidelines advise a bone biopsy in situations where it
would affect continuing treatment for CKD-MBD.
Management
The pathogenesis described above implies that management
should include measures to increase serum calcium, decrease
phosphate and replace deficiencies of both substrate 25-
hydroxyvitamin D and activated calcitriol. Available therapies
are illustrated in Table 1. Caution must be exercised in raising
serum calcium beyond the upper limits as this is associated with
vascular calcification and poor outcomes. All patients should be
offered dietary counselling before initiating treatment. Despite
this, compliance with both dietary measures and binders is
frequently poor and should be checked if serum phosphate is not
responding to therapy.
Therapeutic levers in CKD
Calcium Phosphate
Calcium acetate [ YYY
Calcium carbonate [[ YY
Sevelamer carbonate 4 YY
Lanthanum 4 Y
Iron-based binder 4 YY
Native vitamin D 4 4
Active vitamin D [ [
Calcimimetic Y Y
Lowered dialysate Ca2þ Y 4
The arrows depict the expected response(s) of serum biochemical parameters.
a
May lower PTH in early CKD.
Table 1
MEDICINE 51:3
Hyperphosphataemia is managed using a combination of di-
etary phosphate restriction and oral phosphate binders; the latter
bind dietary phosphate in the intestinal lumen, preventing its
absorption. Agents are generally categorized as calcium-based
phosphate binders (CBPBs) or non-CBPBs. Calcium acetate is
often first line and sevelamer, an exchange resin, and lanthanum
(both non-CBPBs) are common alternatives. All these agents
have limited efficacy, suffering from relatively low potency and
the need to take large doses timed to coincide with meals. Patient
compliance is frequently poor and should be checked if serum
phosphate is not responding to therapy.
CBPBs, in particular calcium carbonate, have been shown to
increase calcium and increase measures of vascular calcification;
however, there is little reliable proof that this increases cardiovas-
cular morbidity or overall mortality. Similarly, sevelamer has been
shown to reduce vascular calcification, but this is not consistent
across studies. Non-CBPBs are less likely to cause hypercalcaemia
but have increased gastrointestinal adverse effects. CBPBs have a
superior impact on BMD compared with their peers.2
New iron-based phosphate binders, such as ferric citrate and
sucroferric oxyhydroxide, are now in use. Ferric citrate has been
shown to decrease the need for erythropoiesis-stimulating agents
and intravenous iron in dialysis patients. Both iron-based agents
exhibit effects on phosphate and PTH similar to conventional
phosphate-binding drugs; sucroferric oxyhydroxide is anecdotally a
more tolerable agent than conventional non-CBPBs because of the
smaller tablet size.
Deficient calcitriol is replaced either by giving calcitriol as an
oral or injectable formulation, or in many cases by giving a cal-
citriol pro-drug, alfacalcidol. This agent is then subjected to 25-
hydroxylation in the liver, yielding calcitriol. Calcitriol adminis-
tration results in increased serum phosphate, so this should be
anticipated and addressed.
Deficiency of the parent compound 25-hydroxyvitamin D should
also be treated. This can be replaced using oral colecalciferol (D3) or
ergocalciferol (D2), which can be given in both oral and intramus-
cular forms. Doses of at least 1000e3000 U/day are required to raise
25-hydroxyvitamin D to sufficient concentrations (>75 nmol/litre).
Co-administration of colecalciferol and calcitriol has not been
shown to consistently raise calcium concentrations in dialysis pa-
tients and is associated with increased BMD.
New active vitamin D compounds have been developed, some
of which, such as paricalcitol, have the potential for more se-
lective action on the parathyroid glands, with less tendency to
PTH raise serum calcium via actions on intestine and bone. Experi-
mental work using these agents has sometimes shown impres-
YY sive evidence of key biomarker reduction (i.e. FGF-23), but proof
YY of an impact on clinical outcomes is not yet evident.
Y Calcimimetic agents are often used to modulate the action of the
Y calcium-sensing receptors on parathyroid cells. These compounds
Y bind to the transmembrane domain of the receptors, resulting in an
4a allosteric modification that increases its sensitivity to calcium. As a
YYY result, the parathyroid cells perceive the extracellular calcium con-
YYY centration as being higher than it really is. Predictably, this leads to a
[ simultaneous reduction of PTH and calcium (and additionally in
patients with CKD stage 5, elevation of phosphate).
Oral cinacalcet has proved an extremely effective means of
moving PTH, calcium and phosphate into the desired target ranges
when given to patients with hyperparathyroidism and CKD. It
186 Ó 2022 Published by Elsevier Ltd.
 CHRONIC KIDNEY DISEASE
should be taken with a main meal to increase its efficacy and reduce
the gastrointestinal adverse effects. However, its use has been
limited by gastrointestinal adverse effects and compliance issues.
Etelcalcetide is now in routine use; it is given intravenously,
which can help with compliance and avoid adverse effects.
Evocalcet, an oral calcimimetic, has shown non-inferiority to
cinacalcet in trials, with fewer gastrointestinal adverse effects.
Should secondary hyperparathyroidism progress, tertiary hy-
perparathyroidism can necessitate parathyroidectomy. Surgical
treatment in these cases improves both MBD biomarkers and
clinical outcomes. Hypercalcaemia can be present in tertiary
disease, and calcimimetics are often used as a to bridge to sur-
gery, or in place of surgery if the latter is not an option.
The other challenge in CKD is the management of osteopo-
rosis. General principles of management include advising
weight-bearing exercise as this has shown clear benefits on
BMD in CKD patients, including those on dialysis. Bisphosph-
onates, as described above, can contribute to low bone turn-
over, especially in dialysis patients, and should therefore
generally be avoided in advanced CKD. The anti-osteoclast
monoclonal antibody denosumab is not excreted by the kid-
neys so has been reported to be safe in patients with CKD stages
3 and 4. However, there have been reports of severe hypo-
calcaemia in dialysis patients.
Teriparatide, a PTH analogue, may have benefit in increasing
bone turnover in adynamic bone disease; however, its utility is
limited by the need to administer it as daily subcutaneous in-
jections, and its impact on clinical outcomes in this population
remains to be seen. Another anabolic agent is romosozumab
(recently licensed in the UK), a monoclonal antibody against
sclerostin, which is an inhibitor of osteoblast function. This agent
causes a sustained reduction in bone resorption markers and
calcium, with an increase in BMD, and has been used in some
studies in patients with CKD on dialysis.
Biochemical targets in patients with CKD
Observational studies have led to the development of several sets
of guidelines and biochemical targets relating to bone and min-
eral metabolism in CKD, in the hope of improved clinical out-
comes.3 Calcium, phosphate and 25-hydroxyvitamin D should be
maintained within normal ranges.
PTH should be maintained in or just above the normal range
in patients with CKD stage 1 who are not on dialysis. In CKD
stage 5 patients on dialysis, the most recent guidelines recom-
mend supraphysiological (2e9 times the upper limit of normal)
concentrations of PTH. The aim is to set PTH in a range most
likely to be associated with normal or near-normal bone turn-
over, and to avoid the extremes of adynamic bone disease or
hyperparathyroid bone disease.
Although it has to be accepted that the use of PTH as a surrogate
marker of bone turnover is imprecise, it remains the best compro-
mise between utility and feasibility in clinical practice. Guidelines
are keen to focus on a trend of PTH rather than isolated readings; i.e.
if the trend is upwards, increased therapy is needed.
Bone disease after renal transplantation
Despite transplantation, these individuals still have a higher
fracture risk than the general population. This is partly because
MEDICINE 51:3
of glucocorticoid and anti-calcineurin use after transplantation,
and partly undoubtedly because of pre-existing MBD as well as
other factors, as high pre-transplant PTH predicts poor outcomes.
These contribute to osteodystrophy and osteoporosis, which in
turn increases fracture risk and mortality in these patients.
Phosphate concentrations are often low in the post-
transplant period, driven by a persistent elevation of FGF-23
and PTH e the latter remains high in nearly 45% of trans-
plant recipients and represents a significant risk factor for
fracture. If vitamin D is deficient, replacement is currently
recommended in the absence of hypercalcaemia as it can also
play a role in acute cellular rejection. Cinacalcet has been
shown to be effective in reducing PTH in transplant recipients in
the absence of adverse effects on the transplanted kidney.
Osteoporosis can be treated with bisphosphonates or denosu-
mab; and although these can induce low bone turnover, frac-
ture risk reduction is demonstrable in patients with CKD stages
2e4. DXA scanning can be used to assess BMD.
Clinical outcomes
An overall shortcoming in the CKD-MBD literature is a lack of
reporting on outcomes such as mortality, progression to end-
stage renal failure, fragility fractures or cardiac events. Many
studies focus on biomarker change (as some have predicted
outcome well) and measure vascular calcification (often using
different scoring methods), rather than clinical outcomes, which
can make it difficult to reach definitive recommendations.
Very large cohort studies have looked at the influence of
vitamin D therapies on survival and other outcomes. Good evi-
dence emerged that treatment with active vitamin D compounds
is associated with significantly increased in life expectancy
among dialysis patients. However, new data testing vitamin D
receptor activators in dialysis patients without raised PTH con-
centrations have shown no overall benefit in all-cause mortality
or cardiovascular events; there is also a potential trend towards
increased harm in individuals treated with vitamin D receptor
activators, suggesting that the correct strategy is to wait for PTH
to rise before initiating an activator.4
In the case of calcimimetics, analysis of data from a series of
comparative studies has shown a 10-fold reduction in para-
thyroidectomy rate and a 50% reduction in fracture rate among
individuals treated with cinacalcet, compared with those treated
conventionally. The A Randomized Study to Evaluate the Effects
of Cinacalcet plus Low-Dose Vitamin D on Vascular Calcification
in Subjects with Chronic Kidney Disease Receiving Haemodial-
ysis (ADVANCE) study demonstrated a modest reduction in
cardiac calcification scores in participants treated with a combi-
nation of cinacalcet and low-dose vitamin D. A large prospective
study, Evaluation of Cinacalcet Therapy to Lower Cardiovascular
Events (EVOLVE), demonstrated a significant reduction in PTH,
but this was not matched by a significant reduction in death or
cardiovascular events.
The future of CKD-MBD
Vitamin K deficiency in CKD is common and worsens with CKD
stage, not rebounding after transplantation. Recent work has
highlighted its vital role in mediating osteoclast activity and
suggested that vitamin K supplementation may be a potential
187 Ó 2022 Published by Elsevier Ltd.
 CHRONIC KIDNEY DISEASE

route to decreasing fracture risk, as has been shown in animal reduction in trials. It could potentially be used in conjunction
models. with other conventional phosphate binders. A
Burosumab is a monoclonal antibody against FGF-23 and has
been used in X-linked hypophosphataemia with good results.
KEY REFERENCES
However, it increases serum phosphate, and its application in
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CKD-MBD remains unclear despite FGF-23 being key to CKD-
kidney disease-mineral and bone disorders: pathogenesis and
MBD pathogenesis.
management. Calcif Tissue Int 2021; 108: 410e22.
A study examining angiotensin II blockade, which combined
2 Phannajit J, Wonghakaeo N, Takkavatakarn K, et al. The impact of
clinical observation with in vitro and in vivo work, showed that
phosphate lowering agents on clinical and laboratory outcomes in
patients on angiotensin II receptor blockers had a reduced risk of
chronic kidney disease patients: a systematic review and meta-
fragility fractures, with the animal model showing that angio-
analysis of randomized controlled trials. J Nephrol 2022; 35:
tensin II activity negatively affected bone elasticity.5 Angiotensin
473e91.
II blockers are commonly used in CKD for their reno-protective
3 Erratum. Kidney disease: improving global outcomes (KDIGO)
qualities in proteinuric patients, so work examining their effect
CKDMBD update work group 2017 clinical practice guideline up-
on CKD-MBD parameters is ongoing.
date for the diagnosis, evaluation, prevention, and treatment of
Sodium-glucose co-transporter 2 (SGLT2) inhibitors are
chronic kidney disease-mineral and bone disorder (CKD-MBD).
increasingly used in patients with CKD with or without diabetes
Kidney Int Suppl 2017; 7: 1e59.
mellitus. As use continues to rise, consideration must be given to
4 J-DAVID Investigators; Shoji T, Inaba M, Fukagawa M, et al. Effect
their role in increasing phosphate, FGF-23 and PTH concentra-
of oral alfacalcidol on clinical outcomes in patients without sec-
tions as well as reducing calcitriol. No increased risk of fracture
ondary hyperparathyroidism receiving maintenance hemodialysis:
was identified in large-scale trials including patients with renal
the J-DAVID randomized clinical trial. J Am Med Assoc 2018; 320:
impairment, but longer term analyses of their impact on these
2325e34.
outcomes will be helpful to clarify their potential impact.
5 Wakamatsu T, Iwasaki Y, Yamamoto S, et al. Type I angiotensin II
Tenapanor is a novel pan-phosphate transporter inhibitor that
receptor blockade reduces uremia-induced deterioration of bone
has shown good tolerability and effective phosphate and PTH
material properties. J Bone Miner Res 2021; 36: 67e79.

TEST YOURSELF
To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the
end of the issue or online here.

Question 1 Investigations.
A 40-year-old man presented after a fall and pain in his left hip.  Calcium 2.24 mmol/litre (2.20e2.60)
He was found to have a fractured neck of femur. He had a history  Phosphate 1.1 mmol/litre (0.8e1.4)
of chronic kidney disease stage 5 and was on maintenance hae-  Estimated glomerular filtration rate 42 ml/minute/1.73 m2
modialysis. He was taking regular alfacalcidol, colecalciferol and (>90)
cinacalcet.  25-Hydroxyvitamin D 33 nmol/litre (45e90)
 Parathyroid hormone 4.3 pmol/litre (1.6e6.9),
Investigations.
 Dual-energy X-ray absorptiometry scanning showed oste-
 Calcium 2.14 mmol/litre (2.2e2.6)
oporotic scores in the vertebrae
 Phosphate 1.4 mmol/litre (0.80e1.50)
 Parathyroid hormone 10 pmol/litre (1.6e6.9) She is advised to take 25-hydroxyvitamin D replacement and
 25-Hydroxyvitamin D 109 nmol/litre (>75) calcium supplementation.

What is the most appropriate additional treatment?

What is the likely bone abnormality in this patient?
A. Denosumab
A. Adynamic bone disease
B. Alfacalcidol
B. Brown tumour
C. Bisphosphonates
C. Osteoporosis
D. Teriparatide
D. Tertiary hyperparathyroidism
E. Strontium ranelate
E. High turnover bone resorption

Question 2
An 83-year-old woman presented with a recent vertebral wedge
fracture at L2 found incidentally on an abdominal X-ray while
she was attending the emergency department with abdominal
pain. She had type 2 diabetes and was needle phobic.
Question 3
A 52-year-old woman presented with bone pain. She had a long
history of advanced renal failure secondary to hypertension. She
was being treated with peritoneal dialysis while awaiting trans-
plantation. She had had a previous non-ST elevation myocardial

MEDICINE 51:3 188 Ó 2022 Published by Elsevier Ltd.

 CHRONIC KIDNEY DISEASE

infarction, treated with primary coronary intervention. She was What is the best next step in her management?
taking high-dose alfacalcidol once daily and high-dose sevelamer A. Start cinacalcet
with her meals. B. Increase the sevelamer dosage
C. Reduce the alfacalcidol dosage
Investigations.
D. Start ferric citrate
 Calcium 2.63 mmol/litre (2.2e2.6)
E. Refer her for parathyroidectomy
 Phosphate 1.74 mmol/litre (0.80e1.50)
 Parathyroid hormone 141.2 pmol/litre (1.6e6.9)
 25-Hydroxyvitamin D 91 nmol/litre (>75)

MEDICINE 51:3 189 Ó 2022 Published by Elsevier Ltd.