The rationale for intermittent administration of PTH in the management of mineral and bone disorder of chronic kidney disease.

A major complication of chronic kidney disease is the derangement of mineral metabolism, leading to increased risk of fractures and cardiovascular mortality. Current therapeutic regimens are focused on reducing parathyroid hormone levels caused by secondary hyperparathyroidism, and the active vitamin D metabolite l,25(OH)2D, with limited success. It may be a more effective approach, however, if we could target the delayed response of parathyroid hormone in the early retention of phosphate following loss of renal function.We propose intermittent administration (even in stage 2 chronic kidney disease) of parathyroid hormone, known for its bone anabolic effects compared to the catabolic effects of the continuously elevated parathyroid hormone associated with the hyperparathyroid state, to mitigate the retention of phosphate. This approach may prevent the compensatory responses of the other two major calcium- and phosphate-regulating hormones (FGF-23 and l,25(OH)2D) that lead to further worsening of the derangement of mineral metabolism.In addition to its strong theoretical basis, there are data supporting the need for further research focused on the use of intermittent parathyroid hormone in the management of chronic kidney disease-mineral bone disorder.

Osteoporosis and Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD): Back to Basics.

Osteoporosis is defined as a skeletal disorder of compromised bone strength predisposing those affected to an elevated risk of fracture. However, based on bone histology, osteoporosis is only part of a spectrum of skeletal complications that includes osteomalacia and the various forms of renal osteodystrophy of chronic kidney disease-mineral and bone disorder (CKD-MBD). In addition, the label "kidney-induced osteoporosis" has been proposed, even though the changes caused by CKD do not qualify as osteoporosis by the histological diagnosis. It is clear, therefore, that such terminology may not be helpful diagnostically or in making treatment decisions. A new label, "CKD-MBD/osteoporosis" could be a more appropriate term because it brings osteoporosis under the official label of CKD-MBD. Neither laboratory nor noninvasive diagnostic investigations can discriminate osteoporosis from the several forms of renal osteodystrophy. Transiliac crest bone biopsy can make the diagnosis of osteoporosis by exclusion of other kidney-associated bone diseases, but its availability is limited. Recently, a classification of metabolic bone diseases based on bone turnover, from low to high, together with mineralization and bone volume, has been proposed. Therapeutically, no antifracture treatments have been approved by the US Food and Drug Administration for patients with kidney-associated bone disease. Agents that suppress parathyroid hormone (vitamin D analogues and calcimimetics) are used to treat hyperparathyroid bone disease. Antiresorptive and osteoanabolic agents approved for osteoporosis are being used off-label to treat CKD stages 3b-5 in high-risk patients. It has now been suggested that intermittent administration of parathyroid hormone as early as CKD stage 2 could be an effective management strategy. If confirmed in clinical trials, it could mitigate the retention of phosphorus and subsequently the rise in fibroblast growth factor 23 and may be beneficial for coexisting osteoporosis.

The CKD-MBD Syndrome: Hysteresis in PTH Involvement and PTH Administration for Its Management.

Chronic kidney disease (CKD) disturbs mineral homeostasis, leading to mineral and bone disorders (MBD). CKD-MBD is a significant problem and currently available treatment options have important limitations. Phosphate retention is thought to be the initial cause of CKD-MBD but serum phosphate remains normal until the late stages of CKD, due to elevated levels of the phosphaturic hormone fibroblast growth factor-23 (FGF-23), and parathyroid hormone (PTH). Reduction of 1,25-dihydroxy-vitamin D (1,25[OH]2 D) concentration is the next event in the adaptive response of the homeostatic system. We argue, and provide the rationale, that calcium retention which takes place concurrently with phosphate retention, could be the reason behind the hysteresis in the response of PTH. If indeed this is the case, intermittent administration of PTH in early CKD could prevent the hysteresis, which arguably leads to the development of secondary hyperparathyroidism, and provide the platform for an effective management of CKD-MBD. © 2020 American Society for Bone and Mineral Research (ASBMR).

Current Understanding of Mineral and Bone Disorders of Chronic Kidney Disease and the Scientific Grounds on the Use of Exogenous Parathyroid Hormone in Its Management.

Chronic Kidney disease (CKD) disturbs mineral homeostasis leading to mineral and bone disorders (MBD). Serum calcium and phosphate (Pi) remain normal until the late stages of CKD at the expense of elevate fibroblast growth factor-23 (FGF-23), a phosphaturic hormone, followed by reduced 1,25-dihydroxy-vitamin D (1,25[OH]2D) and finally elevated parathyroid hormone (PTH). Pi retention is thought to be the initial cause of CKD-MBD. The management of MBD is a huge clinical challenge because the effectiveness of current therapeutic regimens to prevent and treat MBD is limited. An intermittent regimen of PTH, when administered at the early stages of CKD, through its phosphaturic action, could prevent FGF-23 increases, the drop of 1,25(OH)2D, and the development of renal osteodystrophy, including secondary hyperparathyroidism (HPT) and its catabolic effects on the skeleton. Even in more advanced stages of CKD that have not progressed to tertiary HPT, could be beneficial. Therapeutic effects could be achieved in vascular calcification as well. Limited experimental/clinical data support the effectiveness of PTH in CKD-MBD. Its safety, has been established only when it is used for the treatment of osteoporosis, including patients with CKD. The proposed intermittent PTH administration is biologically plausible but its effectiveness and safety has to be critically assessed in long term prospective studies in patients with CKD-MBD.

Oral bisphosphonate use and age-related macular degeneration: retrospective cohort and nested case-control study.

Our objective here was to determine whether oral bisphosphonate (BP) use is associated with the incidence of age-related macular degeneration (AMD). We performed a population-based study using electronic health records from UK primary care (Clinical Practice Research Datalink). A cohort of 13,974 hip fracture patients (1999-2013) was used to conduct (1) a propensity score-matched cohort analysis and (2) a nested case-control analysis. Hip fracture patients were aged ≥50 years without AMD diagnosis before hip fracture date or in the first year of follow-up. Among 6208 matched patients and during 22,142 person-years of follow-up, 57 (1.8%) and 42 (1.4%) AMD cases occurred in BP users and non-BP users, respectively. The survival analysis model did not provide significant evidence of a higher risk of AMD in BP users (subhazard ratio: 1.60; 95% confidence interval (CI): 0.95-2.72; P = 0.08), although there was a significant increased risk among BP users with high medication possession ratio (MPR) (top quartile) relative to non-BP users (odds ratio: 5.08, 95% CI: 3.11-8.30; P < 0.001, respectively). Overall, oral BP use was not associated with an increased risk of AMD in this cohort of hip fracture patients, although the risk increased significantly with higher MPR. More data are needed to confirm these findings.

Osteoporosis treatment: bisphosphonates reign to continue for a few more years, at least?

The findings of the Women's Health Initiative study in 2002 marginalized the use of hormone replacement therapy and established bisphosphonates as the first line of treatment for osteoporosis.  Denosumab could be used in selected patients. Although bisphosphonates only maintain the structure of bone complete with any accumulated structural or material faults, their bone selectivity and effectiveness in reducing the risk of fractures, together with their low cost, have left little room for improvement for new antiresorptives. The osteoanabolic teriparatide increases new bone formation, but it is administered for up to 2 years only and the cost remains a consideration. Similar restrictions are expected to apply to an anti-sclerostin antibody, which could be evaluated by the U.S. Food and Drug Administration in the near future. Cathepsin K-inhibiting antibody could be an alternative if approved; although an antiresorptive, it maintains bone formation, in contrast with bisphosphonates, and can be probably used for long-term treatment.  Rare adverse effects of bisphosphonates, namely osteonecrosis of the jaws and atypical femoral fractures, have been disproportionally emphasized relative to their benefits/harm ratio. Treatment of osteoporosis is a long process, and many patients will require treatment with more than one type of drug over their lifetime.

Calcium supplements controversy in osteoporosis: a physiological mechanism supporting cardiovascular adverse effects.

Recently, administration of calcium supplements for the prevention and treatment of osteoporosis has become a highly controversial issue. The findings of epidemiological studies are not necessarily supportive of the practice and are also open to different interpretations. In this article, we attempt to broaden the discussion and provide evidence that calcium supplementation may fail to compensate for renal calcium loss, and also that the resultant increased calcium load in the circulation could lead to extraskeletal deposition, including in the coronary arteries.

Anabolic effects of PTH and the 'anabolic window'.

Maximization of the anabolic effects of intermittent administration of parathyroid hormone (PTH) has recently been at the forefront of clinical research in the area of osteoporosis, with the 'anabolic window' concept as its main driving force. The outcome of these attempts, however, has not been encouraging. This article examines whether the concept itself is based on sound evidence, related pathophysiological aspects, and whether the new anti-sclerostin antibodies could have extended anabolic action.