Bisphosphonates in renal patients

Supervised by : Prof. Ahmed Gaber

Presented by : Noha Alaa El Dine

Pharm D student

Bisphosphonates in:

ESRD (on HD)CKD stage 2-4

(Rheumatology practice on glucocorticoids with concomitant CKD)

Bisphosphonates

Indications

• Hypercalcemia associated with Neoplasm

•Osteolytic Bone Metastases of Breast Cancer

•Osteolytic Lesions of Multiple Myeloma

•Paget's Disease of Bone

• Bone Metastases

Bisphosphonates are the only US FDA approved therapeutic agents for the treatment of osteoporosis in :

•Postmenopausal women

•Men

•Glucocorticoid-induced osteoporosis (GIOP)

Bisphosphonates

Contraindications

Most Significant Aseptic Necrosis of Jaw Bone, Pregnancy

Significant Dehydration, Renal Disease

Possibly Significant Hypocalcemia, Hypokalemia, Hypomagnesemia, Hypophosphatemia, Thyroid Surgery

Mechanism of action of Bisphosphonates

Bisphosphonates bind to hydroxy apatite and powerfully impair resorptive activity (antiresorptive therapy), and thus reduce bone turnover rate.

In the CKD population, and in particular in those withadvanced disease on dialysis, bone turnover rates varyover a wide range, with a substantial proportion of thepopulation manifesting extremely low bone turnover.

These patients with adynamic bone disease haveimpaired ability to buffer calcium loads, a tendency tohypercalcaemia, as well as increased fracture rates andprevalence of soft tissue calcification. It is quitepossible that these disturbances are further impairedfollowing administration of bisphosphonates to thissubgroup.

Bisphosphonates

In stage 5 CKD, the use of bisphosphonates in

adynamic bone disease and osteomalacia are potentially harmful in the first group and contraindicated in the second group.

Bisphosphonates

Thus, the first decision is to make the discrimination between osteoporosis or nonosteoporosis bone disease in patients with CKD or ESRD.

Bisphosphonates

How Is the Diagnosis of Osteoporosis Made in Patients with CKD or ESRD?

The diagnosis of osteoporosis is based on BMD criteria established in 1994 by The World Health

Organization (WHO; T score of -2.5 or lower) or the presence of the fragility fractures.

However, these criteria cannot be used to diagnose osteoporosis in the patient with CKD or ESRD because all of the various forms of renal osteodystrophy

that are not osteoporosis also have low T scores and may develop fragility

fractures

It can be done to some degree by biochemical profiling measuring in particular

the parathyroid hormone (PTH) level the bone-specific alkaline phosphatase (BSAP)

To be truly accurate in the diagnosis, double tetracycline-labeled quantitative bone histomorphometry is the best diagnostic test, since each specific form of renal bone disease is defined by specific criteria established by standard committees on nomenclature

Bone biopsy

How Is the Diagnosis of Osteoporosis Made in Patients with CKD or ESRD?

The only way to make the diagnosis of osteoporosisin a patient with CKD or ESRD is by excluding

the other forms of renal osteodystrophy.

How is the exclusion done?

Adynamic bone disease

Adynamic bone disease

Adynamic bone disease may have reversible etiologies For the ESRD patient with adynamic bone disease, this low bone turnover may be reversible if the factor(s) responsible for the low bone turnover is removed (excess PTH suppression by vitamin D metabolites or possibly even cinacalcet, for example).

Adynamic bone disease

It is important to point out that adynamic bone disease, does not occur in the earlier stages

of CKD.Adynamic renal bone disease may be seen in advance stages of CKD, with levels of GFR reductions so severe that it really is ESRD.

CKD stage 2-4

Yet because adynamic bone disease is not seen before ESRD levels of renal failure (stage 5), for the patient in a rheumatology practice on glucocorticoids with concomitant CKD, where the physician wants to start a bisphosphonate to prevent steroid-induced bone loss or fractures, the potential presence of adynamic bone disease should not be a concern.

Bisphosphonates in:

ESRD (on HD)CKD stage 2-4

(Rheumatology practice on glucocorticoids with concomitant CKD)

Dose of BisphosphonatesThe length of use of bisphosphonatesThe rate of infusion of IV bisphosphonate.

What Are the Considerations in Bisphosphonate Utilization in CKD in the Patient with Osteoporosis

Bisphosphonates are excreted by filtration and tubular secretion.

Oral bisphosphonates are generally poorly absorbed by the gastrointestinal tract, but what does get absorbed usually has potent bone effects to inhibit bone resorption.

Of the amount absorbed, 50% attaches to bone and 50% is excreted by the kidney.

Bisphosphonates are not dialyzed

Dose of Bisphosphonates

ESRD patients with osteoporosis and are having fragility fractures or who are receiving chronic glucocorticoids, that they should receive 50% of the FDA approved dosing

Dose of Bisphosphonates

Bisphosphonates accumulate in bone due to their exceptional affinity to the calcium–phosphorus crystal surface as well as their diffusion into the bone matrix.

BPs are re-released from the bone after their attachment & reentry of BPs back into the circulation is not only from detachment from bone surfaces but also to release from the osteoclast.

It is unknown as to whether the bone retention time and bone accumulation of BP increases as renal clearance decreases.

The length of use of bisphosphonates

The length of use of bisphosphonates

Limit treatment to 2–3 years based on the re-cycling BP data that have been accumulated, and the unknown but probable greater bone retention of BPs in this population.

The rate of infusion of IV bisphosphonate

Intravenous pamidronate has been associated with the development of a chronic renal lesion: focal glomerular sclerosis.

Intravenous zolendronate has been associated with the induction of acute renal failure, most likely because of the renal-cell lesion of acute tubular necrosis.

To date, intravenous ibandronate has not been associated with the development of any renal disease.

The administeration of IV BPs much slower at the same dose

The rate of infusion of IV bisphosphonate

30 minutes to 1 hour for

zolendronic acid

4 hours for pamidronate

Dose of BisphosphonatesThe length of use of bisphosphonatesThe rate of infusion of IV bisphosphonate.

What Are the Considerations in Bisphosphonate Utilization in CKD in the Patient with Osteoporosis

Commercially available bisphosphonates

Alendronate: Fosamax®, Bonapex®, Osteomax®, Alendomax®, Osteomepha®

Oral Etidronate: Ossidron®, Etidron® OralRisedronate: Actonel® OralClodronate: Bonefos® IV & OralPamidronate: Aredia® IV onlyZoledronic acid: Zometa ®, Aclasta ®

Precautions for Administration

The major side effect of oral bisphosphonates is gastric irritation, which manifests as nausea vomiting and dyspepsia.

Hence these agents should be taken with a glass of water and the patients should remain upright for at least 30 minutes after ingestion.

If patients cannot be upright for 30 minutes due to any physical ailment, then oral bisphosphonates are contraindicated.