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REVIEW

C URRENT
OPINION Agents to treat osteoporosis in chronic kidney
disease
Pascale Khairallah

Purpose of review
Fracture risk is significantly elevated in patients with chronic kidney disease (CKD), yet the diagnosis and
treatment of CKD-associated osteoporosis remain complex. This review addresses the current gaps in
managing bone health in CKD and highlights emerging strategies in this high-risk population.
Recent findings
Diagnosis of CKD-associated osteoporosis requires integration of imaging, bone turnover markers, and
occasionally bone biopsy. Correction of mineral metabolism disturbances is foundational, while bone-
targeted therapies must be carefully selected. Treatment strategies are informed by bone turnover status.
Antiresorptives such as bisphosphonates and denosumab are used in high-turnover disease, and
osteoanabolic agents such as teriparatide and romosozumab are promising for low-turnover disease.
Summary
Management of osteoporosis in CKD requires individualized approaches based on bone turnover and
mineral metabolism status. While several pharmacologic options exist, evidence from randomized trials in
CKD populations is limited. Further research is needed to guide treatment selection, define well tolerated
therapeutic targets, and improve skeletal outcomes in this vulnerable group.
Keywords
antiresorptive therapy, bone turnover, chronic kidney disease–mineral bone disorder, osteoanabolic agents,
osteoporosis

INTRODUCTION used for the management of osteoporosis in patients

Chronic kidney disease–mineral bone disorder with CKD and end-stage kidney disease (ESKD),
(CKD-MBD) is a term that refers to the abnormalities highlighting areas in need of further investigation.
in mineral metabolism, skeletal health, and soft The management of osteoporosis in kidney trans-
tissue calcifications that affect patients with kidney plant recipients is beyond the scope of this review.
disease, contributing to increased fracture risk,
increased cardiovascular death and overall poor DIAGNOSIS OF CHRONIC KIDNEY
DISEASE ASSOCIATED OSTEOPOROSIS
&&
outcomes [1 ]. Individuals with CKD experience
fracture rates up to five times higher than the gen- Patients with CKD stage 3 and above and those who
eral population, leading to significant morbidity
have evidence of mineral abnormalities are at high
and mortality [2,3]. The risk of fractures in patients
risk of osteoporosis. CKD-associated osteoporosis
with CKD is increased due to abnormalities in bone
can be diagnosed by a combination of imaging,
strength. Bone strength is defined by bone mass and
bone turnover markers and/or bone biopsy (Table 1).
bone quality. CKD-associated osteoporosis is a term
Fracture prediction is important to risk-stratify
developed to distinguish osteoporosis in patients
patients with CKD-MBD who would benefit from
with CKD from postmenopausal osteoporosis and
osteoporosis in the general population where
Department of Medicine, University of California, San Francisco,
defects in bone quality and increased risk of fracture California, USA
are present sometimes in the absence of marked Correspondence to Pascale Khairallah, MD, MS, Assistant Professor,
&&
reductions in bone mass [1 ]. Department of Medicine, University of California San Francisco, San
There is an urgent need for effective fracture Francisco, CA 94110, USA.
prevention in patients with CKD, yet current man- E-mail: [Link]@[Link]
agement of CKD-associated osteoporosis remains Curr Opin Nephrol Hypertens 2025, 34:397–407
challenging. This review explores current therapies DOI:10.1097/MNH.0000000000001091

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supports peak bone mass in growing adults, but

KEY POINTS evidence on its role in fracture prevention is limited.
Fall prevention is recommended in older individuals

CKD-associated osteoporosis requires a tailored
and those at risk for falls [7]. Adults at least 65 years
diagnostic and therapeutic approach distinct from that
of the general population. of age with CKD, and patients on dialysis are at
increased risk of falling as compared to older adults

Management of mineral metabolism disturbances without CKD [8].
remains foundational for preserving bone health in
CKD.

Antiresorptive therapies, including bisphosphonates and PHARMACOLOGIC INTERVENTIONS FOR
denosumab, are effective in early CKD but must be THE MANAGEMENT OF CHRONIC KIDNEY
used cautiously in advanced stages. DISEASE ASSOCIATED OSTEOPOROSIS

Anabolic agents such as teriparatide and romosozumab Pharmacologic interventions aimed at the manage-
may benefit patients with low-turnover bone disease, ment of CKD-associated osteoporosis focus on two
though data in CKD are limited. key aspects: controlling the metabolic abnormalities
of CKD-MBD and using agents that directly target

Evidence guiding osteoporosis treatment in advanced
bone.
CKD and dialysis is limited, highlighting the need for
dedicated clinical trials.
Management of mineral metabolism
disturbances
antifracture therapy. Bone mineral density (BMD) Disturbed mineral metabolism is an important
testing through DXA is a widely available and cost- driver of CKD-associated osteoporosis, with secon-
effective method of screening patients for CKD-asso- dary hyperparathyroidism (SHPT) playing a central
ciated osteoporosis. DXA gives information on bone role in the pathogenesis of skeletal abnormalities in
density and volume and predicts fractures in CKD. It patients with kidney disease. Triggers for hyper-
does not however give information on turnover and parathyroidism include hypocalcemia, hyperphos-
mineralization. Bone turnover markers can then aid phatemia and low vitamin D levels, therefore,
BMD testing, adding information regarding bone interventions aimed at mitigating these metabolic
&&
turnover [4 ]. In patients in whom there are still abnormalities are critical to control parathyroid
uncertainties regarding bone turnover state, a bone hormone (PTH) levels.
biopsy is necessary. Based on identification of risk,
and knowledge of bone turnover state, treatment can Calcium, phosphorus, and vitamin D
then be targeted. Management consists of a combi- control
nation of nonpharmacological interventions, the Hypocalcemia is the most important driver for PTH
correction of mineral metabolism disturbances and secretion, making the maintenance of normal cal-
the administration of bone-targeted therapies. Bone- cium levels crucial for controlling hyperparathyr-
targeted agents including antiresorptives are reserved oidism [9]. Concerns about the risk of calcium
for patients diagnosed with high bone turnover while supplementation and potential positive calcium
anabolic agents are reserved for patients diagnosed balance driving vascular calcification and increased
with low bone turnover. cardiovascular death led to the practice of avoidance
of calcium supplementation in patients with kidney
&&
disease [1 ]. However, this practice of avoidance of
NON-PHARMACOLOGIC INTERVENTIONS calcium and “permissive hypocalcemia” in patients
FOR THE MANAGEMENT OF CHRONIC with kidney disease can be suspected to have inad-
KIDNEY DISEASE ASSOCIATED vertently led to worsening of skeletal health. A
OSTEOPOROSIS European Consensus Statement supports increasing
Nonpharmacologic interventions should be the calcium intake up to 1500 mg in patients with CKD
first-line therapy in all patients with CKD-associated in order to maintain a neutral calcium balance [10 ].
&

osteoporosis as a significant amount of the variance KDIGO CKD-MBD Controversies Conference pub-
in BMD can be explained by environmental factors, lished in 2025 noted that “Recommendations for
mainly nutrition [5]. Diets deficient in calcium, calcium intake should be personalized, considering
proteins or vitamin D impair bone quality. Smoking, the state of mineral metabolism, overall calcium
excessive alcohol use, and low BMI are well known balance, current medical therapy, and bone and
risk factors for osteoporosis [6]. Physical activity &&
vascular health” [1 ].

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Hyperphosphatemia increases bone resistance intake and the risk of excessive intake remains
to PTH and decreases osteocyte viability, which all unclear.
&&
affect bone quality [1 ]. Hyperphosphatemia is also Vitamin D supplementation is recommended in
an important trigger for hyperparathyroidism [11]. CKD patients with vitamin D deficiency or insuffi-
The control of hyperparathyroidism specifically ciency. Vitamin D is important for normal matrix
with calcium-based phosphorus binders may trans- mineralization and for controlling SHPT which itself
late into improved BMD [12]. Further, the use of has deleterious effects on bone [9,14]. Kidney guide-
calcium-based phosphorus binders may be associ- lines recommend targeting a 25(OH)D level more
ated with a reduction in fracture risk in retrospective than 30 ng/ml (75 nmol/l) aligning with the recom-
&&
studies [13]. This effect of calcium-based phospho- mendations in the general population [1 ,15]. Data
rus binders specifically is likely due to the increase in are lacking as to whether this target goal should be
calcium intake associated with these binders, result- the same in all CKD stages.
ing in improved skeletal mineralization. However, It is recommended to add low-dose active vitamin
the optimal balance between adequate calcium D to nutritional vitamin D in order to control

Table 1. Diagnostic methods and fracture risk assessment tools in chronic kidney disease

Tool/Method Assessment Advantages Limitations

FRAX [85–89] Estimates 10-year probability of major
Calibrated in 78 countries.
Does not account for falls.
osteoporotic and hip fractures (with/
Considers competing mortality
May under-estimate risk in
without BMD). risk. CKD.

Simple and accessible.
Limited validation in CKD
stages 4–5D.

CKD not yet included as a
specific risk factor.
DXA [24,90,91] Measures BMD to define osteoporosis
Strong predictor of fracture risk
Low T-score may reflect
and fracture risk. in CKD and non-CKD. conditions other than

T-score widely used. osteoporosis (e.g.
osteomalacia).

T-score cutoff (< -2.5) not
always aligned with clinical
risk in CKD
Trabecular Bone Score Provides surrogate measure of
Adds independent value beyond
Mixed results in CKD patients.
[92,93] trabecular microarchitecture from BMD and FRAX.
Further research needed in
DXA spine images.
FRAX-adjusted TBS available. CKD.
HR-pQCT [93–96] High-resolution imaging of cortical and
Captures cortical and trabecular
Limited to peripheral sites
trabecular microstructure (e.g., detail. (radius, tibia).
porosity, failure load).
Noninvasive, longitudinal
Similar predictive value to
monitoring. DXA.

Finite element modeling adds
Limited availability to research
predictive strength. centers.
18F-NaF PET [97,98] Assesses regional bone turnover and
High sensitivity.
Radiation exposure.
osteoblast activity; also evaluates
Correlates with
High cost and limited access.
vascular calcification. histomorphometry.
Experimental tool at this time

Useful in monitoring therapy.
Bone Biopsy Gold standard to classify renal
Detailed insight into bone
Invasive and costly.
(Histomorphometry) osteodystrophy based on turnover, pathology, including static and
Limited availability and
[24,99] mineralization, and volume dynamic parameters, expertise.

Essential in complex cases (e.g.,
Interpretation is complex and
before certain treatments). time-consuming.
Bone Turnover Markers Reflect bone formation/resorption
Easily obtained from blood.
Interpretation affected by CKD-
(PTH, BALP, PINP, activity; used to monitor turnover and
Some (e.g. TRaP5b, intact PINP) related factors.

PTH is not a direct turnover
&&
TRaP5b) [4 ] treatment effect. less affected by CKD.
marker.

Biomarker cut-offs vary and
may lack precision for fracture
prediction.

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hyperparathyroidism in advanced CKD and end-stage limitations, calcimimetics appear to improve BMD
&&
kidney disease [1 ]. Despite these recommendations, and lower fracture incidence and as such may be an
the current evidence from RCTs is insufficient to important therapeutic option for managing bone
associate nutritional or VDRAs with fracture preven- health in the ESKD population.
tion or improvement in BMD in CKD [16–18]. Addi- Etelcalcetide, Upacicalcet, and Evocalcet are
tionally, there is no evidence to determine whether newer generation calcium-sensing receptor (CaSR)
different formulations of vitamin D have different agonists that are administered intravenously. Intra-
dose-response relationships in different CKD stages. venous calcimimetics can improve compliance and
Importantly, excess supplementation is also associ- reduce pill burden in the population on dialysis. They
ated with development of adynamic bone disease, are also associated with greater declines in PTH levels
hypercalcemia, and hyperposphatemia [19]. as compared to cinacalcet [29]. In CKD-SHPT animal
models, etelcalcetide improved mineral homeostasis
Calcimimetics and parathyroidectomy and bone strength, upacicalcet suppressed ectopic
SHPT in patients with CKD increases bone resorp- calcification and cortical pore formation, and evo-
tion affecting both trabecular and cortical bone, and calcet reduced cortical porosity and decreased osteo-
increases fracture risk [20,21]. The Kidney Disease cyte death [30–32]. In a single-arm, open-label, 36-
Improving Global Outcomes (KDIGO) guidelines do week prospective trial, participants on hemodialysis
not recommend a PTH target for patients with CKD with SHPT who were administered intravenous etel-
stages 3 to 5, but propose maintaining PTH levels calcetide had an increase in the areal BMD at the
approximately two to nine times the upper limit of spine, femoral neck, and total hip by 3%  1%, 7%
normal in patients on dialysis, whereas the Japanese  2%, and 3%  1%, respectively (P < 0.05) by DXA;
Society of Nephrology recommends serum intact increase in spine trabecular bone score and increase
PTH targets of 70 pg/ml or less up to CKD stage 3, in radius stiffness and failure load as assessed by
100 pg/ml or less for stage 4, and 100–300 pg/ml for HRpQCT. Bone biopsy demonstrated a decreased
stages 5 and 5D [22–24]. However, these recom- bone formation rate. This pilot study was the first
mended targets were put in place from observational to demonstrate improvement in BMD in patients
studies and no randomized controlled trials compar- receiving etelcalcetide; however, only a limited num-
ing different PTH targets with skeletal outcomes or ber of patients underwent a bone biopsy, and the
mortality have been done to date. When PTH levels study duration was insufficient to assess fracture out-
&
remain outside the recommended range despite comes [33 ]. Larger, long-term studies are needed to
correction of hypocalcemia, hyperphosphatemia, evaluate the effects of intravenous calcimimetics on
and vitamin D deficiency, treatment options skeletal outcomes and to directly compare their effi-
include calcimimetics or parathyroidectomy. cacy on bone health with that of oral calcimimetics.
Calcimimetics are calcium-sensing receptor ago- Calcimimetics are associated with gastrointesti-
nists which suppress PTH secretion. Additionally, nal side effects, including nausea and vomiting [34].
they may have a direct anabolic effect on bone by They can also lead to hypocalcemia which can be
acting on calcium-sensing receptors expressed in mitigated with vitamin D and calcium supplemen-
osteoblasts, potentially promoting bone formation tation [35,36]. Careful monitoring of calcium status
independent of PTH reduction [25]. Cinacalcet is an is advisable when prescribing calcimimetics.
oral calcimimetic whose administration increases While this review focuses on pharmacologic
femoral neck BMD compared to placebo and is agents for managing CKD-associated osteoporosis,
associated with decreased bone formation [26]. In parathyroidectomy remains an important consider-
the EVOLVE placebo-controlled trial that random- ation for treating secondary and tertiary hyperpar-
ized 3883 hemodialysis patients with SHPT to athyroidism. Observational studies suggest that
receive cinacalcet or placebo, cinacalcet reduced patients who undergo parathyroidectomy experi-
the rate of clinical fracture by 16–29% [27]. In a ence improved BMD at the spine and hip, along with
meta-analysis of randomized controlled trials reduced fracture rates compared to those with CKD
including 6481 dialysis patients with SHPT, the and ESKD who do not undergo surgery [37–39].
administration of calcimimetics halved fracture Following parathyroidectomy, patients should be
incidence compared to placebo or conventional monitored for hungry bone syndrome, which affects
treatment [relative risk (RR): 0.50, 95% confidence up to 20% of those undergoing the procedure [40].
interval (95% CI) 0.29–0.88, P ¼ 0.02]. Calcimimet- Hungry bone syndrome presents with severe, some-
ics demonstrated a number needed to treat of only times prolonged hypocalcemia due to rapid skeletal
47 patients to prevent an incident fracture. Varia- uptake of calcium, phosphorus, and magnesium
tions in PTH levels and calcimimetic dosages were following the removal of the hyperactive parathy-
&
observed among the studies [28 ]. Despite study roid glands. It can be minimized by preoperative

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optimization of vitamin D levels, and careful post- nonnitrogen-containing bisphosphonate group.

operative calcium and vitamin D supplementation. On the other hand, alendronate, ibandronate,
pamidronate, risedronate, and zoledronate, are
Calcimimetics vs. parathyroidectomy known as a nitrogen-containing bisphosphonates.
In the first head-to-head study comparing calcimimet- Bisphosphonates inhibit farnesyl pyrophosphate
ics to parathyroidectomy, Wang et al. [41 ] random- synthase in osteoclasts. This crucial enzyme in the
&&

ized 65 peritoneal dialysis patients with advanced synthesis of isoprenoid compounds is necessary for
SHPT to either total parathyroidectomy with forearm osteoclast function [46].
autografting or cinacalcet for 12 months. Both treat- Oral bioavailability of bisphosphonates is low,
ments improved BMD at the lumbar spine and femoral with most drug taken up by bone and the remainder
neck, but the parathyroidectomy group had a signifi- excreted via the kidneys [46,47]. Bisphosphonates
cantly greater increase in BMD (P < 0.001). Osteope- can be retained in the skeleton for several years, and
nia/osteoporosis rates at the femoral neck decreased can re-enter the circulation during cycles of bone
more in the parathyroidectomy group (78.2 to 51.7%, remodeling. Since excretion is mainly through the
P < 0.001) than in the cinacalcet group (65.7 to 52.0%, kidneys, bisphosphonates accumulate in the setting
P ¼ 0.7). Similar trends were seen at the lumbar spine. of CKD. This has led to significant concerns against
Parathyroidectomy also resulted in a more rapid and their use in patients with eGFR less than 30 ml/min,
&&
pronounced PTH decline [41 ]. Beyond skeletal ben- due to concern of their excessive accumulation in
efits, parathyroidectomy appears to improve survival the skeleton, thus resulting in over suppression of
compared to calcimimetics or conservative manage- bone remodeling [48]. Although bisphosphonate
ment in severe hyperparathyroidism. This advantage use is contraindicated at an eGFR less than 30 ml/
may be due to greater PTH suppression and restoration min, these drugs have been given off-label in stud-
&
of PTH pulsatility [33 ,42–45]. ies. Studies have reported that hemodialysis clears
Managing hyperparathyroidism is essential for bisphosphonates, reducing the risk of excessive
preventing osteoporosis and improving bone health accumulation in bone and alleviating concerns
in CKD. However, lowering PTH to normal in our about the development of adynamic bone disease
patients with kidney disease can lead to adynamic [49–51]. For example, administration of alendronate
bone disease. Current guidelines do not define opti- at the beginning of a dialysis session, or ibandronate
mal PTH targets across different CKD stages. There at the end of a session once a month can be reason-
are no RCTs comparing calcimimetics, parathyroi- able administration strategies. Reduced and less fre-
dectomy or vitamin D repletion on bone turnover, quent dosage strategies in nondialysis patients is
mineralization, on fracture events. Further research also reasonable.
is needed to establish evidence-based PTH targets In mild and moderate CKD, bisphosphonates
and to refine treatment strategies for optimizing the are effective and well tolerated resulting in a signifi-
management of SHPT. cant increase in BMD at the hip and lumbar spine
and reduction in fractures [52–54]. Studies in
patients with severely reduced kidney function are
PHARMACOLOGIC INTERVENTIONS sparse and are mainly limited to postmenopausal
DIRECTLY TARGETING BONE women with age-related declines in kidney func-
Treatment of osteoporosis in patients with CKD tion. Similar efficacy in terms on BMD improvement
stages 1–3 is generally similar to that in the general and fracture reduction can be seen as with milder
population. Laboratory abnormalities described forms of CKD [52,54,55].
above should be addressed first, followed by bone- Intravenous bisphosphonates are associated
targeting agent. The use of osteoporosis medications with acute kidney injury which can be mitigated
in patients with CKD stages 4–5D is complex and by slow infusion. Oral bisphosphonates may cause
challenging. The following section reviews the use esophagitis. Both oral and intravenous formulations
of antiosteoporotic agents in the context of kidney have been associated with atrial fibrillation, hypo-
disease (Table 2). calcemia, osteonecrosis of the jaw, and atypical
fractures [56]. Their association with vascular calci-
fication is inconclusive with some studies suggest-
Antiresorptive agents ing worsening while others noting improvement
[57–59]. Bisphosphonates association with CKD
Bisphosphonates progression is similarly inconclusive, as some stud-
Bisphosphonates are used for the treatment of ies report worsening kidney function while others
high bone turnover in patients with kidney dis- find no significant effect [54,60]. Notably, one study
ease. Clodronate and etidronate belong to the linking bisphosphonates to CKD progression also

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Table 2. Agents and interventions used for the management of chronic kidney disease associated osteoporosis

Agent/Intervention Indication CKD Stage Effects Side effects and safety considerations

Calcimimetics Secondary CKD 5D
Suppress PTH secretion
Gastrointestinal side effects (nausea,
hyperparathyroidism
Improve BMD vomiting)

Cinacalcet reduces
Risk of hypocalcemia
fracture risk
No fracture data for IV calcimimetics

IV formulations
improve compliance
Parathyroidectomy Secondary CKD 5D
Rapid PTH suppression
Invasive procedure
hyperparathyroidism
Greater BMD
Risk of hungry bone syndrome
or tertiary improvements than
hyperparathyroidism calcimimetics

May reduce fracture
risk and improve
survival

Bisphosphonates High bone turnover CKD 1–3; Off-
Improve BMD
Contraindicated in eGFR <30 mL/
label CKD 4–5D
May reduce fracture min (but has been used off-label)
risk
Risk of adynamic bone disease if not
dosed properly in CKD4–5D

Hypocalcemia, esophagitis, rare jaw
osteonecrosis

No data on fracture reduction
Denosumab High bone turnover CKD 1–5D
Not renally cleared
Hypocalcemia, especially in CKD 4–

Improves BMD 5D

Rebound bone loss
postdiscontinuation; should be
followed by bisphosphonate upon
discontinuation

Jaw osteonecrosis

No data on fracture reduction
Teriparatide Low bone turnover CKD 1–5D
Increases BMD
Hypercalcemia,
disease, adynamic
Stimulates bone
Hyperuricemia
bone disease formation
Limited biopsy-based data

No data on fracture reduction
Abaloparatide Low bone turnover Potential use in
Higher affinity for
No data in GFR <60 or dialysis
disease, adynamic CKD 1–5D (not transient PTH receptor
No data on fracture reduction
bone disease studied in GFR conformation
(theoretical benefit) <60 ml/min)
Romosozumab Low bone turnover CKD 1–5D
Dual effect: increases
FDA boxed CV warning
disease, adynamic formation, decreases
Use limited to 1 year
bone disease resorption
Rebound bone loss after

Increases BMD discontinuation; should be followed
by bisphosphonate or denosumab
upon discontinuation

No data on fracture reduction

observed a paradoxical reduction in mortality, rais- population. The need for adjusted dosing or shorter
ing the question of whether their potential survival treatment duration in advanced CKD and ESKD
benefits may outweigh the risks of kidney function requires further study, but lower doses or extended
decline [60]. dosing intervals may be valid approaches.
Patients with advanced CKD and kidney failure
are not included in randomized placebo-controlled
bisphosphonate trials, making their use in this pop- Denosumab
ulation off-label. While the efficacy and safety of Denosumab is a mAb that targets the receptor acti-
bisphosphonates in CKD G4–G5D remain unclear, vator of NF-kB ligand (RANKL), inhibiting osteoclast
there is no strong evidence suggesting a less favor- proliferation and development. Unlike bisphosph-
able risk-benefit profile compared to the general onates, it is not cleared by the kidneys, eliminating

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the risk of excessive bone turnover suppression due Randomized controlled trials comparing skeletal
to drug accumulation in CKD [61]. outcomes and fracture rates in patients with CKD
A post hoc analysis of the 3-year FREEDOM study treated with bisphosphonates vs. denosumab are
and 7-year extension study evaluated the long-term lacking. Masuda et al. [71] sought to determine the
effectiveness of denosumab compared to placebo in risk for cardiovascular events and fracture preven-
women aged 60–90 years with mild-to-moderate tion effects with denosumab compared with oral
chronic kidney disease (CKD stages 2 and 3) and bisphosphonates in dialysis-dependent patients over
low bone density (T-score between –2.5 and –4.0) at 50 years old in Japan. The authors estimated that,
the hip or spine. Participants receiving denosumab in compared with oral bisphosphonates, denosumab
all eGFR subgroups showed similar, persistent BMD lowered the risk for fractures by 45% but increased
gains over time and a low incidence of fractures [62]. In the risk for MACE by 36% [71]. Whether this
324 patients with dialysis and nondialysis-dependent increased risk of major adverse cardiovascular events
kidney disease receiving denosumab, annual changes is related to the increased risk of hypocalcemia noted
in BMD at the lumbar spine from baseline were similar in several other studies is unknown at this time and
in hemodialysis (HD) as non-HD patients demonstrat- further studies to confirm these findings are needed.
ing similar efficacy of denosumab regardless of kidney Given its renal safety profile and consistent effi-
function [63]. Denosumab is effective in restoring cacy in improving bone density across CKD stages,
bone mass and reducing bone pain in patients on denosumab represents a valuable treatment option for
dialysis with SHPT [64]. A retrospective study inves- select patients. However, its use must be balanced
tigated the cortical and trabecular compartments and against potential risks, including hypocalcemia,
estimated strength indices of the hip region after a rebound bone loss, and possible cardiovascular events.
maximum of 5 years of denosumab therapy in 124
dialysis patients. After starting denosumab, areal
BMD, cortical volumetric BMD, cortical surface
Osteoanabolic agents
BMD, cortical thickness, trabecular volumetric BMD
and strength indices showed a significantly higher Parathyroid hormone analogues
trend for over 2.5 years, which then stabilized at a Despite hyperparathyroidism being the mainstay of
&
higher value compared with baseline [65 ]. CKD-MBD, most patients with CKD present with low
Denosumab is associated with osteonecrosis of bone turnover. Adynamic bone disease in HD
the jaw and atypical fractures [66]. A major safety patients is due to skeletal resistance to PTH or sup-
issue with denosumab is related to the increased risk pression of PTH release as in patients who undergo
of resorption and fractures after discontinuation. parathyroidectomy, leading to a downregulated
This is noted after discontinuation where cortical bone turnover and bone fracture. PTH exerts direct
and trabecular indices return to pretreatment levels, effects on osteoblasts and osteocytes, in addition to
&
and fracture rates increase [62,65 ,67]. Therefore, for exerting indirect effects on osteoclasts. These effects
patients who receive denosumab, any interruption can differentially lead to bone formation or resorp-
or discontinuation in therapy should be followed by tion. Short duration of exposure stimulates osteo-
a “rescue” plan with a bisphosphonate to prevent bloasts and subsequently bone formation while
accelerated bone resorption [67]. prolonged exposure such as in the case of kidney
Recent studies have highlighted the significant disease leads to increased production of RANKL,
risk of hypocalcemia associated with denosumab, par- stimulation of osteoclasts, and subsequent bone
&
ticularly in patients with advanced CKD [62,68,69 ]. resorption [72]. This understanding has guided the
In a population-based cohort study of adults over 65 development and use of PTH analogs like teriparatide
with newly prescribed denosumab, the incidence of and abaloparatide to treat low-turnover bone disease.
hypocalcemia was as high as 24% in those with eGFR Teriparatide is a recombinant peptide of the first
less than 15 ml/min and 14% in those on maintenance 34 amino-terminal residues of PTH. In patients with
hemodialysis [68]. The 12-week weighted cumulative mild, moderate, and severe CKD. Teriparatide
incidence of severe hypocalcemia was 41.1% with increased BMD at the spine and femoral neck in
&
denosumab [69 ]. Among patients with stages 4 and all kidney function groups [73,74]. In patients with
5 CKD and on dialysis, around 1.53% of patients on ESKD, Teriparatide increased lumbar spine BMD,
denosumab had a risk for emergently treated hypo- improved the monthly change in BMD at both
calcemia [62]. Calcium and vitamin D repletion, mul- the spine and the hip [75]. Malluche et al. [76]
tidisciplinary communication between bone and randomized patients with CKD5D, T-scores of 1 or
kidney specialists, and careful monitoring of calcium less on DXA and low bone turnover to 12 months of
postdenosumab injection for at least 4 weeks, can Teriparatide vs. placebo. Teriparatide as compared
reduce the risk of hypocalcemia [70]. to placebo was found to significantly improve BMD

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as assessed by QCT. The main limitation in this A post hoc analysis of these two trials assessed
study was that low bone turnover was defined using romosozumab patients with mild-to-moderate
bone biomarkers including PTH levels which ranged age-related CKD (GFR 30–59, 60–89, and 90 ml/
from 138 to 337 pg/ml. Bone biopsies were not min). Romosozumab significantly increased BMD at
performed to confirm the diagnosis [76]. In one the lumbar spine, total hip, and femoral neck across
study, the use of Teriparatide in HD patients with all kidney function categories, and reduced the risk
low PTH levels also led to improvement in bone of vertebral fractures in all subgroups [82]. In a
formation and turnover, increased trabecular bone single-center study of 76 Japanese patients on hemo-
mass and increased secretion of endogenous PTH dialysis, one year of subcutaneous administration of
[77]. The use of teriparatide in SHPT can be con- romosozumab (210 mg/4 weeks) resulted in a 3.1%
troversial as it risks increasing cortical porosity [78].  7.2% increase at the lumbar spine and 7.2%
Interestingly though, preclinical studies suggest  8.3% at the femoral neck. In contrast, in 55
that intermittent administration of teriparatide patients who did not receive any romosozumab
may still induce an anabolic bone response, even had no change in their BMD over one year. Romo-
in the setting of SHPT [79]. zosumab was not associated with an increased risk of
Abaloparatide is an analogue of PTH-related cardiovascular events during the 1 year of admin-
peptide designed to have relatively greater affinity istration [83].
for the transient state of PTH1 receptor, thus poten- The FDA has a boxed warning concerning the
tially being more anabolic and theoretically more potential risk of myocardial infarction, stroke and
beneficial in CKD patients with PTH hyporespon- cardiovascular death in patients who use Romosozu-
siveness. ACTIVE, an 18-month, randomized, dou- mab. Due to this risk, its use is currently limited to
ble-blind, active-comparator, placebo-controlled one year only. This risk is of particular concern in our
study of postmenopausal women with osteoporosis CKD and dialysis-dependent patients who are at high
who received subcutaneous abaloparatide 80 mg, risk for cardiovascular events, and patients should be
placebo, or open-label teriparatide 20 mg daily, carefully selected for romosozumab therapy. Similar
included patients with creatinine up to 2.0 mg/dl. to denosumab, a bone turnover rebound and rapid
Patients with eGFR 25 to less than 60 ml/min who bone loss have been observed after romosozumab.
received abaloparatide and teriparatide had similar Hence patients who discontinue romosozumab
fracture rates to those who received placebo. Those should be placed on an antiresportive medication.
with eGFR at least 60 ml/min who received abalo- Data on sequential therapy indicate that romosozu-
paratide or teriparatide had significant reductions in mab followed by denosumab may be a promising
fracture rates as compared to patients who were regimen for the treatment of osteoporosis [84].
randomized to placebo [80]. To date, there are no As with other agents used in the treatment of
data on the use of abaloparatide in patients under- CKD-associated osteoporosis, there are no random-
going dialysis. ized controlled trials showing reduction in fracture
Adverse events include transient hypotension rates after treatment with anabolic agents.
and hypercalcemia and hyperuricemia, which were
more common in patients with the lowest levels of
creatinine clearance [77]. MONITORING AFTER THERAPY
In osteoporosis management, a treat-to-target
Romosozumab approach often aims for a T-score above 2.5; how-
Sclerostin is a glycoprotein product of the SOST ever, its applicability in CKD populations requires
gene, secreted by osteocytes. Sclerostin inhibits further validation. In non-CKD patients, improve-
Wnt signaling, which is a key negative regulator ments in BMD as assessed by DXA account for up to
of bone formation, therefore, inhibition of sclero- 80% of the reduction in fracture risk, underscoring
stin favors bone formation over resorption. Romo- BMD’s role as both a risk factor and treatment goal
sozumab, a human mAb against sclerostin was [15]. Bone turnover markers, which respond more
developed as an antiosteoporotic agent with dual rapidly to therapy than BMD, can reflect treatment
activity, promoting bone formation and inhibiting effects in both CKD and non-CKD patients. They are
bone resorption [81]. In patients with kidney dis- valuable tools for guiding and monitoring therapy
ease, its use is recommended for patients with low (Fig. 1).
bone turnover, promoting bone formation.
Data from the FRAME trial and the ARCH trials
established the efficacy of romosozumab in increas- CONCLUSION
ing BMD and decreasing the risk of verterbral frac- The pathophysiology of CKD-associated osteoporo-
tures in patients with postmenopausal osteoporosis. sis is complex, and the absence of robust evidence

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Agents to treat osteoporosis in chronic kidney disease Khairallah

FIGURE 1. Algorithm to monitor drug therapy in osteoporosis. aAntiresorptives decrease bone resorption markers (TRACP-5b),
and eventually formation markers (P1NP, BSAP). PTH Analogues increase bone formation and bone resorption markers.
Romosozumab increases bone formation and decreases bone resorption markers, leading to uncoupling of bone remodeling.

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