Alendronate Versus Denosumab in Kidney Transplant Patients
Condition: Osteoporosis, Osteopenia; Renal Transplant Recipient
MeSH terms: Osteoporosis; Bone Diseases, Metabolic
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      The management of bone disease has often been neglected post-transplantation, when the
      clinical focus is on allograft function and immunological sequelae. However, most renal
      transplant recipients (RTRs) have pre-existing CKD-MBD, which results in changes to mineral
      metabolism and reduced bone mineral density (BMD) and quality, which are linked to an
      increased incidence of fractures and cardiovascular disease. Bone loss is greatest in the
      first 6-12 months post-transplantation, during which period any intervention is likely to be
      of greatest benefit. Anti-resorptive agents all inhibit bone resorption. Since
      bisphosphonates and densoumab are the most widely used anti-resorptive agents for
      osteoporosis, we conduct this prospective interventional comparative study to compare the
      efficacy and tolerability of alendronate versus denosumab in de novo kidney transplant
      recipients with reduced bone mineral density, in the first 12 months treatment after kidney
      transplantation.
    

Detailed description: 
      Patients with chronic kidney disease (CKD) exhibit a complex form of bone disease defined by
      KDIGO as "Mineral and Bone Disorder" (CKD-MBD). CKD-MBD generally encompasses two
      pathological disorders, namely vascular calcification and renal osteodystrophy, which is the
      bone health impairment associated with chronic kidney disease. Among the complications
      associated with renal osteodystrophy, hip or vertebral fractures are associated with an
      increase in morbidity and mortality in patients with end-stage kidney disease.

      CKD-MBD is a systemic disease that links disorders of mineral and bone metabolism due to CKD
      to either one or all of the following: abnormalities of calcium, phosphorus, parathyroid
      hormone or vitamin D metabolism; abnormalities in bone turnover, mineralization, volume,
      linear growth or strength; or vascular or other soft-tissue calcification. Consequently,
      since bone status in recently transplanted patients reflects several years of CKD-MBD, it
      would be useful to assess bone status in this population.

      The management of bone disease has often been neglected post-transplantation, when the
      clinical focus is on allograft function and immunological sequelae. However, most renal
      transplant recipients (RTRs) have pre-existing CKD-MBD, which results in changes to mineral
      metabolism and reduced bone mineral density (BMD) and quality, which are linked to an
      increased incidence of fractures and cardiovascular disease. Pre-existing renal
      osteodystrophy, including adynamic bone disease, is further affected post-transplantation by
      the use of immunosuppressive medications (glucocorticoids and calcineurin-inhibitors),
      variable renal allograft function and post-transplantation diabetes mellitus.

      Successful renal transplantation corrects many metabolic abnormalities associated with the
      development of renal osteodystrophy. However, osteopenia and osteoporosis remain prevalent,
      even in patients with well-functioning grafts. Increasing attention has focused on preventing
      late complications of transplantation and on patient quality of life by addressing factors
      affecting long-term morbidity, such as cardiovascular risk, post-transplantation diabetes
      mellitus, cancer, and bone disease.

      The spectrum of bone diseases in kidney transplant recipients includes renal osteodystrophy,
      osteoporosis, bone fracture, and osteonecrosis. Earlier studies after transplantation
      indicate that BMD declines by 4%-10% in the first 6 months, with a further decrease of
      0.4%-4.5% in lumbar BMD between 6 and 12 months. After 1 year, BMD remains relatively stable
      with no further decline but at significantly lower levels than healthy controls. This
      reduction in BMD contributes to an increased risk of fractures.

      Osteoporosis is defined as skeletal disorder characterized by compromised bone strength with
      low BMD and bone quality predisposing to an increased risk of fracture and bone fragility.
      Osteoporosis has also been defined quantitatively using BMD and can be expressed as standard
      deviation (SD) score comparing an individual's BMD with that of a reference population as
      measured by dual x-ray absorptiometry (DEXA). A T-score that is ≤ -2.5 is indicative of
      osteoporosis.

      In RTRs, a noninvasive cost-effective tool regarding diagnostic evaluation of osteoporosis is
      BMD monitoring with DEXA scans. BMD is the amount of bone mass per unit volume (volumetric
      density), or per unit area (areal density), and both can be measured in vivo by densitometric
      techniques. A wide variety of techniques is available to assess bone mineral that are
      reviewed elsewhere. The most widely used are based on X-ray absorptiometry of bone,
      particularly dual energy X-ray absorptiometry, since the absorption of X-rays is very
      sensitive to the calcium content of the tissue of which bone is the most important source.

      DEXA is obtained by aiming two radiograph beams with different energy levels at the patient's
      bones. After subtracting the soft tissue absorption, the BMD is determined. DEXA is the most
      widely used noninvasive technique for measuring BMD in the general population. Low BMD by
      DEXA is a robust and consistent risk factor for fracture and treatments that increase BMD
      reduce fracture risk.

      Bone mineral density is most often described as a T- or Z score, both of which are units of
      SD. The T-score describes the number of SDs by which the BMD in an individual differs from
      the mean value expected in young healthy individuals. The Z-score describes the number of SDs
      by which the BMD in an individual differs from the mean value expected for age and sex. It is
      mostly used in children and adolescents.

      Bone loss is greatest in the first 6-12 months post-transplantation, during which period any
      intervention is likely to be of greatest benefit. Anti-resorptive agents all inhibit bone
      resorption. The FDA-approved anti-resorptive agents include calcitonin, estrogens, selective
      estrogen receptor modulators, bisphosphonates and denosumab. Each anti-resorptive agent has
      each owns unique mechanism of action. Since bisphosphonates and densoumab are the most widely
      used anti-resorptive agents for osteoporosis, these two agents will be focused here.

      There is strong evidence that bisphosphonates prevent post-transplantation bone loss;
      however, data are lacking that this clearly extends to a reduction in fracture incidence.
      Denosumab is a potential alternative to vitamin D receptor agonists and bisphosphonates in
      reducing post-transplantation bone loss; however, further studies are needed to demonstrate
      its safety in patients with a significantly reduced estimated glomerular filtration rate
      (eGFR). Clinical judgement remains the cornerstone of this complex clinical problem,
      providing a strong rationale for the formation of combined endocrinology and nephrology
      clinics to treat patients with Chronic Kidney Disease-Mineral and Bone Disorder, before and
      after transplantation.

      Bisphosphonates are chemical analogues of naturally occurring pyrophosphates (P-O-P),
      degradation products of adenosine triphosphate metabolism. Pyrophosphates are rapidly
      metabolized by the ubiquitous presence of pyrophosphatases, while bisphosphonates (P-C-P) are
      not metabolized. Once entering the blood stream, bisphosphonates are rapidly taken up by
      bone, the only tissue that binds bisphosphonates. In bone, bisphosphonates inhibit bone
      resorption by two mechanisms: a physiochemical one stabilizing the calcium-phosphorus surface
      and a cellular one by inhibiting osteoclast activity. Bisphosphonates are cleared by the
      kidney both by filtration and active proximal tubular secretion. Bisphosphonates are retained
      in bone in the remodeling resorption cavity and the amount of bisphosphonate retained in
      probably a function of the baseline remodeling space, the chronic rate of bone turnover and
      the glomerular filteration rate (GFR). While oral bisphosphonates are poorly (less than 1% of
      a single dose) absorbed and 50% of that excreted unchanged by the kidney, intravenous
      bisphosphonate show a 100% bioavailability with still 50% of an intravenous dose excreted by
      the kidney. Treatment with bisphosphonates before and after renal transplantation had a
      favorable effect on BMD, with bisphosphonates, such as pamidronate and alendronate, being
      preferable to other treatments.

      Denosumab is a full length human monoclonal antibody against the receptor activator of
      nuclear factor kappa-B ligand (RANKL), a cytokine that is essential for the formation,
      function, and survival of osteoclasts. By binding RANKL, denosumab prevents the interaction
      of RANKL with RANK on osteoclasts and reversibly inhibits osteoclast-mediated bone
      resorption. It was approved by the U.S. Food and Drug Administration in June 2010 as a new
      treatment for postmenopausal osteoporosis in women who are at high risk of fractures.
      Denosumab is not renally cleared, which makes it more attractive than bisphosphonates in
      patients with significant graft dysfunction, although there are little data of its use in the
      transplant population. Denosumab treatment may be useful to improve bone health in the first
      year after kidney transplantation and was safe except for a higher number of urinary tract
      infections and asymptomatic episodes of hypocalcemia.

      There are no comparative studies of different agents available for treatment of RTRs, who
      remain a heterogeneous population in terms of renal function. However, given that bone loss
      is greatest in the first 12 months, any benefit will be greatest in this period. KDIGO 2017
      guidelines suggest treatment with vitamin D, calcitriol/alfacalcidol, and/or antiresorptive
      agents be considered in patients in the first 12 months after kidney transplant with an
      estimated glomerular filtration rate greater than approximately 30 ml/min/1.73 m2 and low
      BMD.

      Finally, this prospective interventional comparative study will be conducted to compare the
      efficacy and tolerability of alendronate versus denosumab in de novo kidney transplant
      recipients with reduced bone mineral density, in the first 12 months treatment after kidney
      transplantation.
    

Intervention name(s): Denosumab 60 mg/ml [Prolia]; Alendronate 70Mg Tab
Intervention type(s): Drug; Drug
Intervention description(s): full length human monoclonal antibody against the receptor activator of nuclear factor kappa-B ligand; Bisphosphonates
Intervention MeSH terms: Denosumab; Alendronate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Denosumab; Alendronate; Osteoporosis; renal transplant