1. Bisphosphonates in renal patients Supervised by : Prof. Ahmed Gaber Presented by : Noha Alaa El Dine Pharm D student

2. Bisphosphonates in: ESRD (on HD) CKD stage 2-4 (Rheumatology practice on glucocorticoids with concomitant CKD)

3. 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)

4. Bisphosphonates Contraindications Most Significant Aseptic Necrosis of Jaw Bone, Pregnancy Significant Dehydration, Renal Disease Possibly Significant Hypocalcemia, Hypokalemia, Hypomagnesemia, Hypophosphatemia, Thyroid Surgery

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

6. Mechanism of Action: Like etidronate, pamidronate has pharmacologic actions similar to those of pyrophosphate, which occurs naturally in the body and inhibits bone resorption. Bone resorption releases excessive amounts of calcium into the blood. The double phosphonate group common to all bisphosphonates allows them to bind to calcified bone matrix. Adsorption of pamidronate to hydroxyapatite crystals in the mineralized matrix reduces solubility of the matrix and therefore osteoclastic resorption. A stable bone matrix will also prevent signalling to osteoclasts to migrate to the site. Pamidronate blocks attachment of osteoclast precursors to mineralized matrix, preventing transformation into mature, functioning osteoclasts. Pamidronate reduces bone turnover and, when used in combination with adequate hydration to increase renal excretion of calcium, reduces serum calcium concentrations. Serum calcium concentrations, urinary calcium/creatinine ratio, and hydroxyproline/creatinine ratio usually return to within or below normal within the first week after treatment.

7. In the CKD population, and in particular in those with advanced disease on dialysis, bone turnover rates vary over a wide range, with a substantial proportion of the population manifesting extremely low bone turnover. These patients with adynamic bone disease have impaired ability to buffer calcium loads, a tendency to hypercalcaemia, as well as increased fracture rates and prevalence of soft tissue calcification. It is quite possible that these disturbances are further impaired following administration of bisphosphonates to this subgroup. Bisphosphonates

8. 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

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

10. 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

11. 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 osteoporosis in a patient with CKD or ESRD is by excluding the other forms of renal osteodystrophy. How is the exclusion done?

12. Adynamic bone disease

13. 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).

14. 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.

15. 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.

16. Bisphosphonates in: ESRD (on HD) CKD stage 2-4 (Rheumatology practice on glucocorticoids with concomitant CKD)

17. Dose of Bisphosphonates The length of use of bisphosphonates The rate of infusion of IV bisphosphonate. What Are the Considerations in Bisphosphonate Utilization in CKD in the Patient with Osteoporosis

18. 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

19. 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

20. 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

21. 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.

22. 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.

23. 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

24. Dose of Bisphosphonates The length of use of bisphosphonates The rate of infusion of IV bisphosphonate. What Are the Considerations in Bisphosphonate Utilization in CKD in the Patient with Osteoporosis

25. we sorely need evidence-based data to guide clinicians on the proper use of bisphosphonates in patients with CKD and ESRD

26. Commercially available bisphosphonates Alendronate: Fosamax ®, Bonapex ®, Osteomax ®, Alendomax ®, Osteomepha ® Oral Etidronate: Ossidron ®, Etidron ® Oral Risedronate: Actonel ® Oral Clodronate: Bonefos ® IV & Oral Pamidronate: Aredia ® IV only Zoledronic acid: Zometa ®, Aclasta ®

27. 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.