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.

Periodontal Disease, Dental Implants, Extractions and Medications Related to Osteonecrosis of the Jaws.

Patients taking bisphosphonates and other anti-resorptive drugs are likely to attend general dental practice. The term 'bisphosphonate'is often immediately associated with osteonecrosis of the jaws (ONJ). Risk assessment and subsequent management of these patients should be carried out taking into account all the risk factors associated with ONJ. The introduction of newer drugs, also shown to be associated with ONJ, demands increased awareness of general dental practitioners about these medications. CPD/CLINICAL RELEVANCE: This paper provides an update on medication-related ONJ and considers the effects of anti-resorptive drugs on the management of patients needing exodontia, treatment for periodontal disease and dental implant placement.

Safety issues with bisphosphonate therapy for osteoporosis.

Randomized controlled trials have demonstrated the efficacy of bisphosphonates (BP) in improving BMD and reducing fracture risk. Various safety issues that were not noted in clinical trials have, however, now emerged with post-marketing surveillance and increasing clinical experience. The risk of atypical femoral fracture could increase with long-term use of BP, although absolute risk is very small, particularly when balanced against benefits. A drug holiday should be considered after 5 years of treatment for patients at low risk of fracture, although there is no official recommendation regarding this to guide clinicians. Osteonecrosis of the jaw from low-dose BP used for osteoporosis is very rare, and mainly a complication with high-dose i.v. BP used in oncology. The risk of atrial fibrillation too is negligible, and a definite link cannot be established between BP and oesophageal cancer. BP should be avoided in patients with severe renal impairment and during pregnancy and lactation because of limited safety data. Further epidemiological and clinical data are required to establish safety of BP in long-term users (>5 years) and provide evidence-based management.

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.

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.

A review of the literature on osteonecrosis of the jaw in patients with osteoporosis treated with oral bisphosphonates: prevalence, risk factors, and clinical characteristics.

OBJECTIVE: This literature review was performed to elucidate the relationship between bisphosphonate use and development of osteonecrosis of the jaw (ONJ) in patients receiving oral bisphosphonates for the treatment of osteoporosis. METHODS: MEDLINE, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and EMBASE were searched for English-language articles published from 1966 to September 2006 whose titles included the term osteonecrosis of the jaw in conjunction with bisphosphonates, alendronate, risedronate, ibandronate, etidronate, clodronate, zoledronic acid, or pamidronate. Articles were included in the review if the population consisted of adults with ONJ; patients received bisphosphonates for the treatment of osteoporosis only; the reported data included baseline characteristics of the study population (age; sex; comorbidities; concomitant medications; history of dental surgery, trauma, or infection), characteristics of bisphosphonate treatment (specific bisphosphonate, dose, duration of treatment, mode of administration), clinical features of ONJ (signs, symptoms, site), the treatment protocol used to manage ONJ, or the prevalence of ONJ in patients with osteoporosis treated with bisphosphonates; and the publication involved a case report, case series, or observational study. RESULTS: After application of the search strategy and the inclusion/exclusion criteria, 11 publications reporting 26 cases of ONJ in patients receiving bisphosphonates for the treatment of osteoporosis were included in the review. The most commonly affected site was the mandible (16 patients), followed by the maxilla (6 patients). Among the 23 patients whose age was reported, 18 (78%) were aged >or=60 years. Among the 23 patients whose sex was reported, only 3 (13%) were men. Of 15 patients with a history of invasive dental treatment, 12 (80%) had undergone dental surgery or experienced dental trauma at the site of ONJ. Among the 10 patients for whom the duration of bisphosphonate treatment was reported, no clear relationship between the duration of bisphosphonate treatment and the development of ONJ was observed. CONCLUSIONS: Considering that millions of patients have been prescribed bisphosphonates for the treatment of osteoporosis, the relative prevalence of ONJ in these patients was low. Age >or=60 years, female sex, and previous invasive dental treatment were the most common characteristics of those who developed ONJ. However, it is not possible to draw further conclusions about the potential association between oral bisphosphonate use and ONJ in the identified studies because of incomplete reporting and the presence of confounding factors.

Systemic inflammatory mediators and bone homeostasis in intestinal failure.

BACKGROUND: A proinflammatory state has been described in patients with intestinal failure. The prevalence of metabolic bone disease in this group is considerable. It is not known whether this proinflammatory state is related to bone parameters, though bone disease is recognized as a proinflammatory process in postmenopausal women. The purpose of this study was to examine whether inflammation was related to bone disease. METHODS: Eight patients with parenteral nutrition (PN)-dependent intestinal failure but no recent infections or immunosuppressive medications had serum assayed for interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha, and its receptors (TNFR-I and TNFR-II), C-reactive protein, and whole blood for lymphocyte proliferation. Routine clinical laboratory measures of vitamin D, parathyroid hormone, serum calcium, and phosphorus within 3 months of the inflammatory measures were compared by Pearson's correlation to the inflammatory measures. RESULTS: Mean values for calcium, phosphorus, and albumin were normal, but 25-hydroxy vitamin D was reduced and parathyroid hormone and alkaline phosphatase elevated. Serum total calcium was negatively related to TNFR-II, TNF-alpha and positively to T-helper cells. Longer PN dependence was associated with inflammation and negatively with T-helper cells. CONCLUSIONS: These preliminary findings are hypothesis generating only but support an association of low calcium and longer duration of PN with inflammation in patients with intestinal failure. Whether the inflammation results from vitamin D deficiency or the vitamin D deficiency develops secondary to excessive use of activated vitamin D to modulate inflammation from some other cause, such as a component of PN or repeated infectious challenge, requires further study.

Prevention and treatment of osteoporosis in inflammatory bowel disease.

The following are guidelines for evaluation and consideration for treatment of patients with inflammatory bone disease (IBD) after bone mineral density (BMD) measurements. The Crohn's & Colitis Foundation of America (CCFA) has indicated that its recommendations are intended to serve as reference points for clinical decision-making, not as rigid standards, limits, or rules. They should not be interpreted as quality standards.

The effect of anti-TNF-alpha therapy on spinal bone mineral density in patients with Crohn's disease.

Proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha) might be, at least partially, responsible for the development of osteopenia or osteoporosis in Crohn's disease. We investigated whether anti-TNF therapy for Crohn's disease could have any skeletal impact. Therefore, we studied the effects of infliximab, a monoclonal antibody against TNF-alpha with and without bisphosphonates, on spinal bone mineral density (BMD). The effect of corticosteroids was also analyzed. A retrospective cohort analysis was performed on 61 patients with Crohn's disease and low BMD by serial DXA scans. Twenty-three patients were on infliximab and 36 patients were on bisphosphonates. Mean duration between DXA scans was 2.2 +/- 0.99 years. After controlling for corticosteroid use, patients with concurrent infliximab and bisphosphonate treatment exhibited a greater increase in BMD compared to those on bisphosphonates alone (+6.7%/year vs. +4.46%/year, P= 0.045); corticosteroids inhibited this effect (P= 0.025). However, infliximab alone had no effects on BMD. Patients receiving bisphosphonates showed a significant increase in lumbar spine BMD compared to those not on bisphosphonates (+3.97% change in T score/year vs. -3.68%/year, P < 0.0001). Concurrent corticosteroid use significantly inhibited this effect (+2.15%/year vs. +4.97%/year, P= 0.0014). Concurrent infliximab use may confer an additional benefit to that already documented for bisphosphonate use alone; bisphosphonates are beneficial in the treatment of low BMD in patients with Crohn's disease, though corticosteroids may partially inhibit this effect.