Leader in digital CPD Earn 1 for Southern African healthcare professionals free CEU Renal , osteoporosis, or both? What is wrong with my renal patient’s skeleton?

Learning objectives

You will learn: • The impact of progressive chronic (CKD) on fracture incidence and morbidity • The factors that predispose the renal patient to fracture • How bone mineral metabolism is disordered in the renal patient • The treatment of in CKD • The use of osteoporosis drugs in CKD. Professor John Cunningham The Centre for , The Royal Free and University College Medical School, Introduction London The interface between osteoporosis and (CKD) poses a conundrum where specialists and nephrologists approach the management of bone health from different frames of reference, often coming to differing conclusions; this may give rise to suboptimal therapy and treatment inertia in the renal patient.

Not only do traditional risk factors and primary (age-related) osteoporosis affect bone health in the CKD patient, but also the uremic risk factors and other systemic illnesses and drugs; patients are often using numerous medications of various kinds 1 Click here – you need to watch (Figure 1). In many cases, these patients are sarcopenic and experience variations in the video in order to complete blood pressure that lead to increased stumbles and falls, further increasing risk for the CPD questionnaire. fracture.

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© 2021 deNovo Medica AUGUST 2021 I 1 Renal osteodystrophy, osteoporosis, or both?

Primary (age-related) osteoporosis

Uremic Traditional Bone in CKD risk factors risk factors

Systemic illnesses and drugs

Figure 1. Osteoporosis and CKD – an unholy alliance1

It is well Fracture incidence and morbidity impact increase established that with progressive CKD incidence of hip It is well established that incidence of hip Furthermore, there is the problem of the fracture increases fracture increases with age. Renal patients have impact of the fracture on dependency. In with age, however both increased frequency and increased impact terms of an arbitrary scale of dependence renal patients of fracture, with a higher fracture-related related to age, the transient impact of any have increased mortality than non-renal patients. Risk of hip individual fracture is significant but a return frequency and fracture increases at every level of glomerular to normal is dependent of the type of frac- filtration rate (GFR) detriment and in the case ture and, in the case of hip fracture, fewer increased impact of the dialysis patient (CKD 5D), longer dura- patients revert to baseline as they often suc- of fracture, with tion of therapy is consistently associated with cumb to complications thereof (Figure 3). In a higher fracture- increased fracture risk in CKD (Figure 2). Of the context of the CKD patient, the increased related mortality interest, the relative risk of fracture is highest dependence arising from any given fracture than non-renal among the younger population (<45 years) is elevated as compared to the general popu- patients with CKD, but the absolute risk of fracture is lation, reflecting the fact that CKD can be highest in the elderly.2,3 viewed as a process of accelerated ageing.

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Hip fracture incidence per 1 000 pt years Hip fracture 0 <45 45–54 55–64 65–74 76–84 Age General population CKD3a CKD3b CKD4 Haemodialysis Figure 2. Age-related incidence of hip fracture in the general population and with increasing CKD severity2,3

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A B Hip fracture Hip fracture Vertebral fracture CKD Vertebral ageing fracture Forearm fracture Normal Normal Forearm ageing ageing fracture Degree of dependence Degree of dependence Degree

50 60 70 80 90 50 60 70 80 90 Age (years) Age (years) FRAX predicts Figure 3. Impact of individual fracture morbidity on patient dependence in the general population (A) and the fracture impact of CKD on this process (B) probability in all CKD stages but there are the problems of Which factors predispose the renal patient to uncertain effects fracture? of extremes of Factors determining the risk of fracture are massively across renal patients and is not bone turnover depicted in Figure 4. In terms of postural easily measured; bone biopsy is expensive and and it is unknown reflexes, a stumble regularly turns into a fall there are a limited number of centres that whether for the renal patient as they are often sar- have both the technology and expertise to CKD requires copenic and experience episodes of blood properly process these samples. adjustments to pressure instability. Quality of the bone varies conventional FRAX estimates and, if so, to what Quality Density extent Physical composition, architecture, turnover, Determined by peak bone damage accumulation, mineralisation mass and amount of bone loss Bone strength Falls

Soft tissue Postural Fracture padding reflexes

EARN FREE Figure 4. Factors determining risk of fracture CPD POINTS Join our CPD community at BMD as a predictor of fracture risk www.denovomedica.com Bone mineral density (BMD), as deter- as prior dialysis will usually have deranged and start to earn today! mined by DEXA scan, is a good prediction the skeletal status in various ways. FRAX of fracture risk in the non-renal population predicts fracture probability in all CKD and in CKD 2 and 3. The predictive value of stages but there are the problems of uncertain DEXA is still quite good in CKD 4 and 5 and effects of extremes of bone turnover and it is although it still has definite utility in CKD unknown whether CKD requires adjustments 5D, the predictive value is variable. Utility to conventional FRAX estimates and, if so, in the transplanted patient is also variable, to what extent.

AUGUST 2021 I 3 Renal osteodystrophy, osteoporosis, or both?

Disordered bone mineral metabolism in CKD Differences between postmenopausal osteo- Serum phosphate is maintained at near porosis and CKD-mineral and bone disorder normal levels consequent to these increases (CKD-MBD) are summarised in Table 1.4 A in FGF23 and PTH, and only decompen- trajectory of biochemical disorders accom- sates when at very low GFR with advanced pany the progression of CKD (Figure 5). CKD. The increase in FGF23 and PTH

There is a decrease in 1,25(OH)2D3 very early becomes massive at dialysis and at this stage in the development of CKD and, notably, an the increase may become maladaptive, rather adaptive response of a simultaneous increase than adaptive, with off-target effects particu- in FGF23 and (PTH). larly on the cardiovascular system.5

Table 1. Differences between postmenopausal osteoporosis and CKD-MBD4 CKD-MBD ‘Ordinary’ osteoporosis Bone formation High prevalence of adynamic bone disease or very Normal to slightly high high bone turnover Biochemical profiles Abnormal , phosphate, FGF23, BMP7, Klotho, Normal or mildly abnormal 1,25-D, iron, bicarbonate, sclerostin, cytokines Variably related to fractures Predicts fractures Bone loss Mostly cortical Trabecular and cortical Vascular Common Rare

Adaptive Maladaptive FGF23 Although the PTH range for normal Increase bone turnover PTH is seemingly Sclerostin high, it must be remembered Phosphate that there is PTH resistance in the Normal uremic skeleton of the CKD 1,25 (OH) D patient 2 3 Change in plasma parameter

Decrease Klotho 100 <90 <60 <30 <15 eGFR (ml/min/1.73m2) Figure 5. Temporal aspects of disordered mineral metabolism in CKD5

What is the association between PTH concentration and bone turnover in the CKD-MBD skeleton? There is a reasonable association between remembered that there is PTH resistance in bone turnover and PTH concentration in the the uremic skeleton of the CKD patient and CKD-MBD skeleton: there is substantial evidence that unless PTH • 150-600pg/ml - normal bone turnover is maintained at these levels, the development • <150pg/ml - adynamic bone disease and of adynamic bone disease will occur. Both low-turnover and high-turnover bone disease • >600pg/ml - fibrosa. states are associated with vascular calcifica- tion, cardiovascular disease, mortality and Although the PTH range for normal . turnover is seemingly high, it must be

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Biochemical markers of bone metabolism – utility in the CKD patient

Biochemical markers of bone metabolism total ALP and bone ALP possibly have the are much less validated in CKD. This is greatest utility as they are not cleared by the problematic because many of these biomark- kidney, and this is also the case for the bone ers are cleared by the kidney, including the resorption marker tartrate-resistant acid resorption biomarkers N-telopeptide and phosphatase-5b. In general, evidence of the C-telopeptide and the formation biomarkers predictive utility of these bone markers in serum osteocalcin and propeptide type 1 col- terms of what is actually going on histologi- lagen and, depending on the assay used, PTH cally is not particularly good. has some utility. In terms of bone formation,

Treating hyperparathyroidism in CKD The progression of secondary hyperparathy- hyperparathyroidism in CKD. The three prin- roidism is driven by chronic decreased cal- ciples tools are , cium levels and chronic increased phosphate and drugs. There is a theoretical levels, as well as decreased levels of difference between vitamin D treatment and and klotho. Continuous functional demand calcimimetic therapy in that the sustained causes the glands to enlarge, initially due to increase of PTH as observed with vitamin D It is important diffuse hyperplasia which becomes increas- has a net catabolic effect on the skeleton and to avoid the ingly nodular over time, thereby producing lowers BMD. On the other hand, calcimi- development more PTH but also under-expressing for the metic therapy confers intermittent increases of adynamic vitamin D and calcium-sensing receptors in PTH levels, more likely to have an anabolic bone disease (CaSR), with a consequential reduced effi- effect and thereby increasing the BMD. While when treating cacy of calcitriol and calcimimetic therapy.6 active vitamin D treatment works very well to hyperpara- progressively diminish the PTH level, there is thyroidism in CKD It is important to avoid the development a strong chance of developing adynamic bone of adynamic bone disease when treating disease over time (Figure 6).

600 Active Vitamin D

Calcimimetic compound 300 Plasma PTH (pg/ml)

0 1 2 3 4 5 Days EARN FREE Figure 6. Intermittent (calcimimetic) versus continuous suppression (calcitriol) of PTH CPD POINTS Join our CPD community at www.denovomedica.com Further benefit of the effect of calcimimetic in a resistant skeleton, with the consequence therapy on the bone in the case of severe of being underexposed to PTH and the and start to earn today! hyperparathyroidism is illustrated in Figure development of adynamic bone disease. On 7.7 Because of the uremic state of the skel- the other hand, if treating with a calcimimetic eton it is resistant to PTH, and so the effect the PTH is lowered and the effect of PTH on of PTH on the skeleton may be fairly modest the skeleton is reduced, but the CaSR is also even at high concentrations. In the case of activated, which is thought to improve the treatment with calcitriol or a parathyroidec- anabolic activity of bone and reducing the tomy, PTH levels are considerably lowered level of PTH resistance. leading to less activation of the PTH receptor

AUGUST 2021 I 5 Renal osteodystrophy, osteoporosis, or both?

CaM CaSR Bone CaSR

Parathyroid CRF – severe SHP PTH-R CaSR Bone CaSR Calcimimetic PTH Normal/low (CaM) therapy turnover Parathyroid PTH-R CaM CaSR Bone CaSR PTH ROD

Parathyroid PTH-R

PTH Normal turnover

Figure 7. Hormonal control of calcium and phosphate – potential role of CaSR in maintaining anabolic activity in severe hyperparathyroidism7

What is the benefit of calcimimetic therapy – the evidence The severe hyper- parathyroidism The Bonefide study8 examined the changes in patients showed more variable outcomes, group showed the bone histomorphometry from baseline of 110 although mostly had improved bone histol- greatest ben- patients using therapy. Inclusion ogy (Figure 8). efit in terms of criteria were PTH ≥300pg/ml, bAP >20.9ng/ 9 change in bone ml, Ca >8.4mg/dl and biopsy proven high- Post hoc analysis of placebo-controlled turnover bone disease. Three categories of studies on the effect of cinacalcet therapy on quality with cina- patient were identified at entry: severe hyper- bone and mineral outcomes in 1 184 patients calcet therapy and parathyroidism, mild hyperparathyroidism indicate a massive reduction in parathyroid- the mild hyper- and mixed uremic osteodystrophy. The severe ectomy (-93%) and a substantial decrease in parathyroidism hyperparathyroidism group showed the great- fracture rate (-54%). These preliminary results patients exhibited est benefit in terms of change in bone quality were the motivation for the EVOLVE study10 either no change with cinacalcet therapy and the mild hyper- which showed only a modest reduction of or benefit parathyroidism patients exhibited either no 20% for relative risk of fracture. change or benefit. The uremic osteodystrophy

2 Severe hyperparathyroidism 5* Mild hyperparathyroidism 3 Mixed uremic osteodystrophy Severe hyperparathyroidism 13 3 Normal bone histology Adynamic bone Osteomalacia 1 Severe hyperparathyroidism 26** Mild hyperparathyroidism 13* Mixed uremic osteodystrophy Mild hyperparathyroidism 56 13 Normal bone histology 2 Adynamic bone 1 Osteomalacia Severe hyperparathyroidism 2 Mild hyperparathyroidism 2 Mixed uremic osteodystrophy Mixed uremic osteodystrophy 8 4 Normal bone histology Adynamic bone Osteomalacia Baseline End of study * 1 patient with early termination; ** 2 patients with early termination Green lines represent a favourable change, red and orange lines represent less favourable change Figure 8. Bonefide – evolution of histomorphometry during cinacalcet treatment8

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Osteoporosis drugs in CKD The medication used will either stimulate the patients. Bisphosphonates and denosumab formation or inhibit the resorption of bone, have been proven to preserve bone density none of these agents are licenced specifically and reduce fracture risk in CKD 1-4/5. Table for CKD (Table 2). Teriparatide treatment 3 summarises the efficacy and safety of these is often counterintuitive to the nephrologist agents. The safety issues of denosumab and as it is often their goal to reduce PTH levels; bisphosphonates are the same as applies to however, it may be of use in the patient with the general population although of specific adynamic bone disease. Romosozumab has concern to the CKD patient with low GFR not been properly evaluated in the CKD is that these agents can trigger significant population and there are concerns that it hypocalcaemia (denosumab <50-60ml/ may increase vascular calcification, which min/1.73m2) and so calcaemic therapy is is already problematic in the CKD patient. always introduced for the first six to eight Sodium fluoride is never used for CKD weeks to mitigate this effect of treatment.11

Table 2. Osteoporosis drugs Stimulating formation Antiresorptive • PTH (teriparatide) • Bisphosphonates • Sclerostin antagonist (romosozumab) • RANK ligand inhibitors (denosumab) • Sodium fluoride

Bisphosphonates Table 3. Efficacy and safety of osteoporosis drugs in CKD11 and denosumab Efficacy have been proven Renal Safety (post- to preserve bone Drugs Clinical trial Comments retention Preclinical Post hoc (advanced menopausal) density and CKD) reduce fracture Nitrogen- Atypical risk in CKD 1-4/5 Dose containing Yes Yes Fracture ↓ BMD ↑ fracture, ONJ, adjustments? bisphosphonates Ca ↓ GFR ↓ Atypical Beware: offset Denosumab No Yes Fracture ↓ BMD ↑ fracture, ONJ, of effect Ca ↓ Dose BMD ↑ PTH analogues No Yes Fracture ↓ Hypotension adjustments? (in ABD) Max 2 years Yes, low CV adverse Beware: offset Romosozumab Unlikely No data No data PTH only events ↑ Ca ↓ of effect

EARN FREE Thresholds for pharmacological intervention CPD POINTS Recommendations on thresholds for phar- • In the absence of a MOF, a DXA T-score Join our CPD community at macological intervention arise from a recent threshold <−2.5 SD at the lumbar spine 11 www.denovomedica.com review: or hip is recommended, recognising that • CKD patients >50 years of age with a a higher threshold of −2.0 or −1.5 may and start to earn today! prior fragility fracture (major osteoporotic be more appropriate although there is no fracture [MOF]) may be considered for hard data to support this view treatment without the need for further • FRAX country-specific intervention thresh- BMD assessment olds are appropriate in CKD patients.

AUGUST 2021 I 7 Renal osteodystrophy, osteoporosis, or both?

Managing the renal patient’s skeleton – key clinical tips • Is this CKD-MBD, osteoporosis, or both? » Hyperphosphataemia – dietary restric- The default position is that it is probably tion/ both » Vitamin D deficiency - cholecalciferol • Many osteoporosis drugs are different in • Then consider the osteoporosis, almost the CKD patient always favours intervention • First identify and manage the CKD-MBD » CKD stage1-5D; generally treat as with issues ‘normals’, with caveats: » PTH – active vitamin D sterol/ – Diagnostics less robust calcimimetic – Drug side effects less well defined – Risk/benefit less certain.

Key learnings

• CKD is a state of rapid accelerated ageing EARN FREE • Primary osteoporosis likely plays a prominent role in bone fragility in CKD 4-5D CPD POINTS • Traditional risk factors for osteoporosis apply to patients with CKD 4-5D Are you a member of • Longer duration of dialysis therapy is consistently associated with increased fracture risk in CKD Southern Africa’s leading • BMD as assessed by DXA predicts fractures in patients with CKD stages 1-5D digital Continuing • DXA probably underestimates the actual fracture risk in patients with CKD 4-5D, as it does not account Professional Development for impaired bone quality website earning FREE • The consistency of the risk prediction using BMD and bone markers across stages of disease and severity CPD points with access to of the components of CKD-MBD remains to be documented. best practice content?

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Click here to access and submit deNovo Medica’s CPD modules For all Southern African healthcare professionals References Click on reference to access the scientific article 1. Evenepoel P, Cunningham J, Ferrari S, et al. Diagnosis and 8. Behets GJ, Spasovski G, Sterling LR, et al. Bone management of osteoporosis in chronic kidney disease histomorphometry before and after long-term treatment stages 4 to 5D: a call for a shift from nihilism to pragmatism. with cinacalcet in dialysis patients with secondary Find us at Osteoporos Int 2021; Jun 15 [online ahead of print]. hyperparathyroidism. Kidney Int 2015; 87(4): 846-856. 2. Moe SM, Nickolas TL. Fractures in patients with CKD: Time for 9. Cunningham J, Danese M, Olson K, et al. Effects of the action. Clin J Am Soc Nephrol 2016; 11(11): 1929-1931. calcimimetic cinacalcet HCl on cardiovascular disease, 3. Naylor KL, Jamal SA, Zou G, et al. Fracture incidence in adult fracture, and health-related quality of life in secondary DeNovo Medica kidney transplant recipients. Transplantation 2016; 100(1): hyperparathyroidism. Kidney Int 2005; 68(4): 1793-1800. 167-175. 10. Chertow GM, Block GA, Correa-Rotter R, et al. Effect of 4. Ott SM. Postmenopausal osteoporosis. N Engl J Med 2016; cinacalcet on cardiovascular disease in patients undergoing 374(21): 2095-2096. dialysis. N Engl J Med 2012; 367(26): 2482-2494. 5. Kuro-O M, Moe OW. FGF23-αKlotho as a paradigm for a 11. Evenepoel P, Claes K, Meijers B, et al. Natural history of @deNovoMedica kidney-bone network. Bone 2017; 100: 4-18. mineral metabolism, bone turnover and bone mineral density 6. Tominaga Y, Takagi H. Molecular genetics of hyperparathyroid in de novo renal transplant recipients treated with a steroid disease. Curr Opin Nephrol Hypertens 1996; 5(4): 336-341. minimization immunosuppressive protocol. Nephrol Dial 7. Mazzaferro S, Pasquali M. Direct bone effects of Transplant 2020; 35(4): 697-705. deNovo Medica in chronic kidney disease? Kidney Int 2019; 95(5): 1012-1014.

This summary report was compiled for deNovo Medica by Disclaimer Published by © 2021 deNovo Medica Glenda Hardy, Medical Cell Biology (Hons), The views and opinions expressed in the article are those of the presenters and do not necessarily reflect Reg: 2012/216456/07 based on the transcript from the webinar those of the publisher or its sponsor. In all clinical instances, medical practitioners are referred to the 70 Arlington Street, Everglen, Cape Town, 7550 presented by Prof John Cunningham product insert documentation as approved by relevant control authorities. Tel: (021) 976 0485 I [email protected]

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