Bone disease in organ transplant patients: pathogenesis and management

Bone disease is common in recipients of kidney, heart, lung, liver, and bone marrow transplants, and causes debilitating complications, such as osteoporosis, osteonecrosis, bone pain, and fractures. The frequency of fractures ranges from 6% to 45% for kidney transplant recipients to 22% to 42% for heart, lung, and liver transplant recipients. Bone disease in transplant patients is the sum of complex mechanisms that involve both preexisting bone disease before transplant and post-transplant bone loss due to the effects of immunosuppressive medications. Evaluation of bone disease should preferably start before the transplant or in the early post-transplant period and include assessment of bone mineral density and other metabolic factors that influence bone health. This requires close coordination between the primary care physician and transplant team. Patients should be stratified based on their fracture risk. Prevention and treatment include risk factor reduction, antiresorptive medications, such as bisphosphonates and calcitonin, calcitriol, and/or gonadal hormone replacement. A steroid-avoidance protocol may be considered.     

Advancing Nephrology: Division Leaders Advise ASN

New treatments, new understanding, and new approaches to translational research are transforming the outlook for patients with kidney diseases. A number of new initiatives dedicated to advancing the field of nephrology—from value-based care to prize competitions—will further improve outcomes of patients with kidney disease. Because of individual nephrologists and kidney organizations in the United States, such as the American Society of Nephrology, the National Kidney Foundation, and the Renal Physicians Association, and international nephrologists and organizations, such as the International Society of Nephrology and the European Renal Association–European Dialysis and Transplant Association, we are beginning to gain traction to invigorate nephrology to meet the pandemic of global kidney diseases. Recognizing the timeliness of this opportunity, the American Society of Nephrology convened a Division Chief Retreat in Dallas, Texas, in June 2019 to address five key issues: (1) asserting the value of nephrology to the health system; (2) productivity and compensation; (3) financial support of faculty’s and divisions’ educational efforts; (4) faculty recruitment, retention, diversity, and inclusion; and (5) ensuring that fellowship programs prepare trainees to provide high-value nephrology care and enhance attraction of trainees to nephrology. Herein, we highlight the outcomes of these discussions and recommendations to the American Society of Nephrology.     

Safety and tolerability of bazedoxifene in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled phase 3 trial

Summary

Findings from this 5-year phase 3 study of postmenopausal women with osteoporosis showed that bazedoxifene was associated with an overall favorable safety and tolerability profile, with no evidence of endometrial or breast stimulation. Overall, the results at 5?years were consistent with those seen at 3?years.

Introduction

We report safety and tolerability findings from a 5-year randomized, double-blind, phase 3 study of bazedoxifene in postmenopausal women with osteoporosis.

Methods

In the core study, healthy postmenopausal women with osteoporosis (N?=?7,492; mean age, 66.4?years) were randomized to daily doses of bazedoxifene 20 or 40?mg, raloxifene 60?mg, or placebo for 3?years. During the 2-year study extension, the raloxifene 60-mg treatment arm was discontinued after the 3-year database was finalized, and subjects receiving bazedoxifene 40?mg were transitioned in a blinded manner to bazedoxifene 20?mg (bazedoxifene 40-/20-mg group) after 4?years. Safety and tolerability data are reported for subjects in the bazedoxifene 20- and 40-/20-mg and placebo groups; efficacy findings are reported elsewhere.

Results

A total of 3,146 subjects in the bazedoxifene 20- and 40-mg and placebo groups were enrolled in the extension study (years 4 and 5). Overall, the 5-year incidence of adverse events (AEs), serious AEs, and discontinuations due to AEs were similar among groups. The incidence of hot flushes and leg cramps was higher with bazedoxifene compared with placebo. Venous thromboembolic events, primarily deep vein thrombosis, were more frequently reported in the bazedoxifene groups compared with the placebo group. Reports of cardiac disorders and cerebrovascular events were few and evenly distributed among groups. Bazedoxifene showed a neutral effect on the breast and endometrium.

Conclusion

Bazedoxifene was associated with an overall favorable safety and tolerability profile in postmenopausal women with osteoporosis over 5?years of therapy, consistent with findings at 3?years.     

Current concepts and management strategies in chronic kidney disease-mineral and bone disorder

ABSTRACT: The term renal osteodystrophy describes the pathological changes in bone structure in chronic kidney disease (CKD); however, this term fails to describe adequately the adverse changes in mineral and hormonal metabolism in CKD that have grave consequences for patient survival. CKD-mineral and bone disorder (CKD-MBD) is a broader, newly defined term that should be used instead of renal osteodystrophy to define the mineral, bone, hormonal, and calcific cardiovascular abnormalities that are seen in CKD. The new paradigm in the management of renal bone disease is to "think beyond the bones" and strive to improve cardiovascular outcomes and survival. This means treating other aspects of the disease process that go beyond merely controlling parathyroid hormone levels. Primary physicians need to take a proactive approach to the management of CKD-MBD because the disorder begins early in the course of CKD, well before a patient is referred to a nephrologist. This review outlines the evidence behind the understanding of CKD-MBD, its implications for overall mortality, and the latest recommendations for management of CKD-MBD in patients with predialysis CKD.     

Effects of two models of hypercalcemia on renal acid base metabolism

The effects of two models of chronic hypercalcemia on renal acid-base metabolism were studied in rats. In the first series of experiments, rats were rendered hyperparathyroid by the autologous grafting of 20 to 24 parathyroid glands into a single recipient. Hypercalcemia (5.48 +/- 0.03 mEq/liter in high PTH animals, 4.96 +/- 0.06 mEq/liter in pair-fed controls, P less than 0.001) occurred as did metabolic alkalosis (plasma total carbon dioxide 25.44 +/- 0.47 mEq/liter vs. 23.84 +/- 0.57 in controls, P less than 0.05). The rise in total carbon dioxide was in part a renal tubular effect since urine pH was lower (6.77 +/- 0.04 vs. 6.95 +/- 0.04, day 5, P less than 0.01) bicarbonaturia less (165 +/- 26 vs. 283 +/- 28 mumoles/24 hr, day 5, P less than 0.01) and titratable acid (TA) excretion increased (164 +/- 43.4 vs. 48.2 +/- 2.53 mEq/24 hr, day 5, P less than 0.01) in hyperparathyroid animals vs. pair-fed controls. To test the specific role of hypercalcemia versus PTH in this effect, normoparathyroid animals were treated with 1.25 (OH)2 vitamin D3 or SHAM injected, Urinary cAMP was reduced in these animals (0.030 +/- 0.004 mumoles/8 hr) compared to hyperparathyroid rats (0.055 +/- 0.01 mumoles/8 hr P less than 0.05) suggesting differences i PTH levels. Hypercalcemia occurred in 1,25(OH)2 vitamin D treated animals as did increased plasma total carbon dioxide and urinary TA while urinary bicarbonate excretion and urinary pH were reduced. Because hypercalcemia was associated with elevated total carbon dioxide in both models, it is proposed that chronic hypercalcemia stimulated renal acid excretion and in a sustained manner results in metabolic alkalosis, at least in part, on a renal basis.