Therapy of osteoporosis in chronic renal insufficiency

Renal dysfunction leads to serious changes in bone density and mineralization. These irregularities are grouped under the term CKD-MBD (Chronic Kidney Disease – Mineral and Bone Disorder) . A review article published in the Clinical Kidney Journal provides guidance on the management of osteoporosis in CKD patients with reference to current KDIGO recommendations.

The combination of classical risk factors for bone fractures – such as age, weight, physical inactivity – and CKD-specific disturbances of mineral and bone balance poses a clinical challenge [1]. Chronic kidney disease in the long term is often associated with irregularities in phosphate, calcium, FGF-23, PTH, and vitamin D metabolism. A separate guideline on CKD-MBD was revised by KDIGO (Kidney Disease: Improving Global Outcomes) in 2017 and remains current [2]. Since there is an increased risk of fracture in CKD stages 3-5D, the KDIGO guideline recommends bone densitometry by DXA in these patients.

The main therapeutic targets in CKD-MBD include [3]:

Avoid hypercalcemia
Reduce elevated phosphate toward normal range
Keep PTH in the normal range to slightly elevated
Avoid or correct vitamin D deficiency

There are a number of agents available for fracture prevention that are generally safe and effective in CKD stages 1-3 [1]. For CKD stages 4-5D, on the other hand, there is less empirical evidence and use must be carefully weighed in terms of risk-benefit balance. In addition to pharmacotherapy, lifestyle factors are also an important pillar of treatment (Fig. 1).

Calcium and vitamin D

Early diagnosis and treatment of secondary hyperparathyroidism (SHPT) is critical in CKD patients. Elevated PTH (parathyroid hormone) levels and abnormal calcium and phosphate levels are commonly observed from CKD stage 3 onwards and it is estimated that 40-82% of patients in CKD stage 3b/4 have SHPT [4]. Recently, Geng et al. in a large cohort of patients with stage 3-4 CKD, the association between baseline PTH levels and long-term morbidity and mortality risks [5]. It was found that high PTH was an independent risk factor for predicting fractures, vascular events, and death.

Vitamin D deficiency is common in CKD patients – especially in the presence of proteinuria – and is known to be associated with an increased risk of fracture. Vitamin D supplementation should be prescribed early in the course of renal disease. To achieve the desired target level for 25-OH vitamin D, an intake of 800 IU/day has been recommended for CKD patients, although individual dose adjustment may be appropriate [6].

Excessive calcium intake may be harmful in CKD patients, especially in the presence of hypercalcemia, low PTH levels, adynamic bone, concurrent warfarin treatment, and/or existing cardiovascular calcifications [7]. Taking moderate doses (up to 1000 mg/day) of oral calcium in combination with antiresorptive treatment over a 1-year period improved BMD but did not increase the risk of cardiovascular calcification or arterial stiffness [8].

Antiresorptives

A number of findings suggest a continued reduction in fracture risk with bisphosphonates that persists for several years after treatment has ended. Fracture prevention by denosumab has been demonstrated in postmenopausal women with normal renal function and in patients in CKD stages 1-3 for at least 10 years [9,10]. In CKD stages 4-5D, there is a relative contraindication for bisphosphonates, due to impaired renal clearance with risk of systemic accumulation and some case reports of acute renal failure. Therefore, with an eGFR <30 ml/min/1.73^m2, the use of bisphosphonates is not permitted in most countries.

Denosumab is not excreted by the kidneys nor does it have adverse effects on renal function, so it is not contraindicated in CKD stages 4-5D [11]. Several observational studies and a few small RCTs indicate moderate to large effects on BMD without increasing cardiovascular risk, even in end-stage renal disease. However, it should be noted that a rebound effect may occur after denosumab discontinuation and the risk of hypocalcemia is increased [13]. Atypical femur fractures and osteonecrosis of the jaw are rare complications of antiresorptive treatments that are no more common in CKD than in other populations.

Osteoanabolics

Teriparatide and abaloparatide are osteoanabolic drugs for the treatment of osteoporosis in postmenopausal women at high risk of fracture. Post-hoc analyses of pivotal studies showed comparable efficacy in reducing fracture risk and increasing BMD in patients with normal renal function compared with patients with CKD stages 1-3 and normal endogenous PTH levels [14,15]. Regarding safety, teriparatide led to hypercalcemia and hyperuricemia more frequently in CKD patients, but without causing an increased incidence of clinical events such as nephrolithiasis or gout. Therefore, in patients in CKD stages 1-3 at high risk of fracture and without elevated endogenous PTH, treatment with osteoanabolic agents appears to be effective and safe when adequately monitored. For CKD stages 4-5, there is evidence of an increase in BMD from smaller studies, but overall data are limited.

Romosozumab

An observational study regarding one year of treatment with romosozumab in hemodialysis patients showed a beneficial effect on BMD without an increased incidence of cardiovascular events compared with age- and sex-matched controls [16]. However, 61.5% of patients treated with romosozumab were pretreated with bisphosphonates (was discontinued when romosozumab therapy was initiated). A recent post-hoc analysis of data from two pivotal studies showed that the efficacy and safety of romosozumab compared with alendronate or placebo were similar in postmenopausal women with osteoporosis at different levels of renal function [17]. While these data are promising, the numerically higher incidence of adverse cardiovascular events in the romosozumab group urges caution and calls for additional safety data, especially since CKD patients are part of a high-risk group, according to the authors of the review article [18,19]. Furthermore, it is important to note that in patients with stage 4-5D CKD , romosozumab therapy can induce profound hypocalcemia [1].

Menopausal hormone therapy and SERMs.

The hypothalamic-pituitary-gonadal axis is impaired in CKD. Consequently, early menopause or hypogonadism are common in CKD patients. It is believed that hormone replacement therapy (HRT) may play an important role in the treatment of osteoporosis in CKD. But the limited data from RCTs make it difficult to make a clear recommendation for HRT and SERMs in patients with chronic kidney disease [11]. With regard to the benefit-risk profile, an increased cardiovascular risk (including with regard to thromboembolic events) in CKD patients is assessed as critical.

Calcimimetics and parathyroidectomy.

Although there is a lack of high-quality evidence of an effect of cinacalcet on reducing fracture risk in CKD stages 4-5D, post-hoc analyses of placebo-controlled trials suggest that there may be some effects [21]. Another subgroup analysis of the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial suggests that it is advisable to consider calcium balance when treating cinacalcet in patients at high risk of fracture [21].

As for parathyroidectomy, BMD increases after surgery in both primary and secondary hyperparathyroidism, especially in patients with osteoporosis [22,23]. In addition, a large study from the US Renal Data System consistently shows that parathyroidectomy reduces fracture risk in hemodialysis patients [24]. In turn, however, hospitalization rates may increase substantially in the first year after surgery [25].

Take-Home Messages

Calcium and vitamin D are also among the standard strategies used in CKD patients for fracture prevention in osteoporosis and for the treatment and prevention of secondary hyperparathyroidism (SHPT) [26]. With regard to calcium in particular, it is important to weigh up the dosage carefully in order to avoid undesirable side effects. And regarding CKD stages 4-5D, it should be noted that the evidence base is small.
Regarding antiresorptive agents, the evidence suggests that their use in CKD 1-3 is safe and effective [1]. In CKD stages 4-5D, the use of antiresorptives may be beneficial but should be based on individualized assessment until more direct evidence is available for fracture prevention in these patients.
Osteoanabolic agents are effective and safe in patients with stage 1-3 CKD who are at high risk of fracture without elevated endogenous parathyroid hormone (PTH) levels [1]. In patients with stage 4-5 CKD and evidence of adynamic bone, PTH analogues may be considered to reduce fracture risk on an individual basis. Due to the lack of data in this specific population, caution is advised, but a proportion of patients may eventually benefit from anabolic treatment.
That romosozumab appears to result in accentuated BMD increases in cortical bone mass in post-menopausal women is of interest to CKD patients [16]. But the authors of the review paper point out that no clinical trial data are currently available that clearly demonstrate the efficacy of romosozumab in CKD [1].
Due to the limited data from RCTs, a clear recommendation for HRT and SERMs in CKD patients is hardly possible at this stage [1,11].
In some osteoporotic patients with primary or secondary hyperparathyroidism, parathyroidectomy results in an increase in bone mineral density (BMD). In addition, an analysis within the US Renal Data System showed that parathyroidectomy reduces the risk of fracture in hemodialysis patients [24].

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