An update on clinical presentation and responses to therapy of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH).

Pathogenic variants in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report a pooled analysis of clinical and laboratory records of 304 individuals from 145 kindreds, including 20 previously unreported HHRH kindreds, in which two novel SLC34A3 pathogenic variants were identified. Compound heterozygous/homozygous carriers show above 90% penetrance for kidney and bone phenotypes. The biochemical phenotype for heterozygous carriers is intermediate with decreased serum phosphate, tubular reabsorption of phosphate (TRP (%)), fibroblast growth factor 23, and intact parathyroid hormone, but increased serum 1,25-dihydroxy vitamin D, and urine calcium excretion causing idiopathic hypercalciuria in 38%, with bone phenotypes still observed in 23% of patients. Oral phosphate supplementation is the current standard of care, which typically normalizes serum phosphate. However, although in more than half of individuals this therapy achieves correction of hypophosphatemia it fails to resolve the other outcomes. The American College of Medical Genetics and Genomics score correlated with functional analysis of frequent SLC34A3 pathogenic variants in vitro and baseline disease severity. The number of mutant alleles and baseline TRP (%) were identified as predictors for kidney and bone phenotypes, baseline TRP (%) furthermore predicted response to therapy. Certain SLC34A3/NPT2c pathogenic variants can be identified with partial responses to therapy, whereas with some overlap, others present only with kidney phenotypes and a third group present only with bone phenotypes. Thus, our report highlights important novel clinical aspects of HHRH and heterozygous carriers, raises awareness to this rare group of disorders and can be a foundation for future studies urgently needed to guide therapy of HHRH.

Osteoporosis and Fracture Risk among Older US Asian Adults.

PURPOSE OF REVIEW: This review summarizes the current knowledge regarding osteoporosis and fracture among older US Asian adults. RECENT FINDINGS: Asian adults have lower (areal) bone density than non-Hispanic White adults and thus are more likely to be diagnosed and treated for osteoporosis, despite their lower risk of hip fracture. The latter may relate to favorable characteristics in hip geometry, volumetric bone density, and bone microarchitecture; lower risk of falls; and other clinical factors. The fracture risk calculator FRAX accounts for the lower risk of hip fracture among US Asian adults. However, data on major osteoporotic fracture risk remain limited. Fracture rates also vary by Asian subgroup, which may have implications for fracture risk assessment. Furthermore, among women receiving bisphosphonate drugs, Asian race is a risk factor for atypical femur fracture, an uncommon complication associated with treatment duration. Recent clinical trial efficacy data pertaining to lower bisphosphonate doses and longer dosing intervals may be relevant for Asian adults. More research is needed to inform osteoporosis care of US Asian adults, including risk-benefit considerations and the optimal duration of bisphosphonate treatment. Greater evidence-based guidance for primary fracture prevention among US Asian adults will ensure health equity in the prevention of osteoporotic fractures.

In osteoporosis or osteopenia, exercise interventions improve BMD; effects vary by exercise type and BMD site.

SOURCE CITATION: Zhang S, Huang X, Zhao X, et al. Effect of exercise on bone mineral density among patients with osteoporosis and osteopenia: a systematic review and network meta-analysis. J Clin Nurs. 2021. [Epub ahead of print]. 34725872.

In women, bisphosphonate use for ≥3 years vs. <3 months was linked to increased atypical femur fracture risk.

SOURCE CITATION: Black DM, Geiger EJ, Eastell R, et al. Atypical femur fracture risk versus fragility fracture prevention with bisphosphonates. N Engl J Med. 2020;383:743-53. 32813950.

Not etched in bone: the role of osteoclast proton-sensing receptors.

The osteoclast proton-sensing receptors may play a role in osteoclastogenesis or bone resorption. The current study by Kreiger et al. found that in female mice, osteoclast-specific deletion of the gene for OGR1 resulted in increased bone mass, which demonstrates that in some situations this receptor is playing a role. However, there are some inconsistencies because the bone resorption was not reduced in their global knockout mice, and the effects are not seen in both genders or by other investigators. More work should be done to better define the role of OGR1 because acidosis is an important cause of bone loss.

Importance of bone turnover for therapeutic decisions in patients with CKD-MBD.

Patients with chronic kidney disease-mineral and bone disorder (CKD-MBD) frequently have low bone formation rates. A recent review suggested that adynamic bone disease is not always associated with negative outcomes and therefore antiresorptive medications could be used more often. However, there is currently no evidence to support an improvement in fracture risk or mortality in patients with CKD-MBD and low bone turnover who are treated with antiresorptive medication. There is reasonable pathophysiological evidence suggesting that it may even be harmful.

Bone Health Management After Hematopoietic Cell Transplantation: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy.

Bone health disturbances commonly occur after hematopoietic cell transplantation (HCT) with loss of bone mineral density (BMD) and avascular necrosis (AVN) foremost among them. BMD loss is related to pretransplantation chemotherapy and radiation exposure and immunosuppressive therapy for graft-versus-host-disease (GVHD) and results from deficiencies in growth or gonadal hormones, disturbances in calcium and vitamin D homeostasis, as well as osteoblast and osteoclast dysfunction. Although the pathophysiology of AVN remains unclear, high-dose glucocorticoid exposure is the most frequent association. Various societal treatment guidelines for osteoporosis exist, but the focus is mainly on menopausal-associated osteoporosis. HCT survivors comprise a distinct population with unique comorbidities, making general approaches to bone health management inappropriate in some cases. To address a core set of 16 frequently asked questions (FAQs) relevant to bone health in HCT, the American Society of Transplant and Cellular Therapy Committee on Practice Guidelines convened a panel of experts in HCT, adult and pediatric endocrinology, orthopedics, and oral medicine. Owing to a lack of relevant prospective controlled clinical trials that specifically address bone health in HCT, the answers to the FAQs rely on evidence derived from retrospective HCT studies, results extrapolated from prospective studies in non-HCT settings, relevant societal guidelines, and expert panel opinion. Given the heterogenous comorbidities and needs of individual HCT recipients, answers to FAQs in this article should be considered general recommendations, with good medical practice and judgment ultimately dictating care of individual patients. Readers are referred to the Supplementary Material for answers to additional FAQs that did not make the core set.

Structural and Metabolic Assessment of Bone.

The assessment of bone structure and metabolism should focus on the bone strength. Many factors are involved, and although bone density is an important component, it is not the same as bone strength. Other aspects of bone quality include bone volume, micro-architecture, material composition, and ability to repair damage. This chapter briefly reviews some of the methods that can be used to assess both density and quality of bone. Non-invasive measurements of density or structure include dual X-ray absorptiometry (DXA), quantitative computed tomography, ultrasound, and magnetic resonance imaging. DXA is most widely used and has advantages of safety and accessibility, but there are limitations in the interpretation of the results, and in clinical practice positioning errors are frequently seen. Invasive methods are used primarily for research. Samples of bone can be used to measure structure by histology as well as micro-computed tomography and infra-red spectroscopy or backscattered electron microscopy. Force can be directly applied to bone samples to measure the bones strength. Impact microindentation is a new minimally invasive technique that measures bone hardness. Metabolic assessment includes blood and urine tests that reflect diseases that cause bone loss, particularly problems with mineral metabolism. Tetracycline-labelled bone biopsies are the standard for measuring bone formation. Non-invasive biochemical tests of bone formation and resorption can evaluate a patient's skeletal physiology.

Risk of complete atypical femur fracture with Oral bisphosphonate exposure beyond three years.

BACKGROUND: Bisphosphonate (BP) therapy has been associated with atypical femur fracture (AFF). However, the threshold of treatment duration leading to increased AFF risk is unclear. In a retrospective cohort of older women initiating BP, we compared the AFF risk associated with treatment for at least three years to the risk associated with treatment less than three years. METHODS: We used observational data from a large population of female members of an integrated healthcare system who initiated oral BP during 2002-2014. Women were retrospectively followed for incident AFF confirmed by radiologic adjudication. Demographic data, pharmacologic exposures, comorbidity, bone density, and fracture history were ascertained from electronic health records. Inverse probability weighting was used to estimate risk differences comparing the cumulative incidence (risk) of AFF if women discontinued BP within three years to the cumulative incidence of AFF if women continued BP for three or more years, adjusting for potential time-dependent confounding by the aforementioned factors. RESULTS: Among 87,820 women age 45-84 years who initiated BP (mean age 68.6, median T-score - 2.6, 14% with prior major osteoporotic fracture), 16,180 continued BP for three or more years. Forty-six confirmed AFFs occurred during follow-up in the two groups. AFF-free survival was greater for BP treatment < 3 years compared to treatment ≥3 years (p = 0.004 comparing areas under survival curves). At five years, the risk of AFF was 27 per 100,000 (95% confidence interval, CI: 8-46) if women received BP treatment < 3 years and 120 per 100,000 (95% CI: 56-183) if women received BP treatment ≥3 years (risk difference 93 per 100,000, 95% CI: 30-160). By ten years, the risks were 27 (95% CI: 8-46) and 363 (95% CI: 132-593) per 100,000 for BP treatment < 3 and ≥ 3 years, respectively (risk difference 336 per 100,000, 95% CI: 110-570). CONCLUSIONS: Bisphosphonate treatment for 3 or more years was associated with greater risk of AFF than treatment for less than 3 years. Although AFFs are uncommon among BP-treated women, this increased risk should be considered when counseling women about long-term BP use. Future studies should further characterize the dose-response relationship between BP duration and incident AFF and identify patients at highest risk.

Renal insufficiency and bone loss.

PURPOSE OF REVIEW: Patients with chronic kidney disease have a high risk of fractures and no established treatments that have been shown to prevent the bone disease. The physiology of renal osteodystrophy is complex and recently more factors have been found that complicate the mineral metabolism. The recognition that vascular calcifications are related to bone disease has made treatment even more challenging. RECENT FINDINGS: The most exciting new findings relate to the signaling pathways that are seen in kidney disease and how they cause abnormalities in bone physiology. In particular, wnt and activin signaling pathways are seen early in the course of renal disease. The bones react by increasing FGF-23, which targets both renal phosphate secretion and a variety of other systemic effects. Secreted klotho is another newly described hormone with effects on several systems.Clinical studies have focused on treatments for hyperparathyroidism and phosphate, and frustrating limitations of the treatments used for ordinary osteoporosis. SUMMARY: Treatment of bone disease in patients with chronic kidney disease is challenging, and understanding the physiological pathways could lead to novel therapies.

Bones and the sex hormones.

Sex hormones act in multiple ways to maintain a strong skeleton. In men, estrogen regulates cortical bone turnover, but testosterone maintains trabecular turnover. In normal men, sex hormone-binding protein is an independent risk factor for fractures. This led Aleksova and colleagues to measure the sex hormones and their binding protein in men receiving dialysis. Both higher sex hormone-binding globulin and higher total testosterone were associated with prevalent nonvertebral fractures, adding another layer of complexity to renal osteodystrophy.

Renal Osteodystrophy-Time for Common Nomenclature.

PURPOSE OF REVIEW: The term renal osteodystrophy has been used to describe a wide variety of bone problems facing patients with chronic kidney disease (CKD). Here, we review the history of the use of this term. RECENT FINDINGS: Bone disease resulting from CKD was first noticed in 1890. The term "renal osteodystrophy" was used to define the bone disease in 1942. Since then, important discoveries have increased our knowledge of the complexities of bone physiology in these patients. At the same time, secular changes in the disease have occurred. The terms used to describe the bone histological findings have changed as well, reflecting new understanding of the physiological processes. However, since different investigators used the terms in different ways, the need to standardize the nomenclature has become increasingly important. Ongoing international collaboration about nosography will allow more optimal communication among scientists and clinicians as we continue to make new discoveries.

Bone strength: more than just bone density.

The following bone density measurements have limited utility in determining bone strength because they do not include bone quality: microarchitecture, mineralization, ability to repair damage, collagen structure, crystal size, or marrow composition. Patients with kidney disease have poor bone quality. Newman et al. now describe beneficial effects with raloxifene in an animal model of progressive kidney disease. These biomechanical measurements will be important in the development of medications to decrease fractures in patients.

Role of proton receptor OGR1 in bone response to metabolic acidosis?

Chronic metabolic acidosis stimulates bone resorption, resulting in loss of calcium and bicarbonate from bone. Both osteoblasts and osteoclasts sense extracellular H(+) by the G-protein coupled receptor, OGR1, whose activation leads to increased bone resorption as well as decreased bone formation. Krieger et al. examined the effect of OGR1 knockout in mice. They found an unexpected increase in bone resorption, but nevertheless an increase in bone volume linked to enhanced bone formation. This discovery opens a window of opportunity to explore potential new anabolic treatments for patients with low bone mass.

Bone cells, sclerostin, and FGF23: what's bred in the bone will come out in the flesh.

Bone metabolism is linked to systemic diseases, and new research shows that the bone cells have endocrine functions that affect multiple organs. They secrete sclerostin, FGF23, prostaglandins, and osteocalcin. Pereira et al. examined gene expression of cells grown from bone biopsies of adolescents with renal osteodystrophy, as a first step to understanding how the bone-cell abnormalities contribute to cardiovascular and metabolic problems in these patients.

Pharmacology of Bisphosphonates in Patients with Chronic Kidney Disease.

Bisphosphonates are medications which bind strongly to mineral. They are ingested by osteoclasts and inhibit an enzyme necessary for bone resorption. The gastrointestinal absorption is poor and the only method of excretion is renal. Therefore, in patients with CKD the body accumulates a higher percentage of a dose of bisphosphonate. These medications remain attached to bone mineral for many years. Although the primary action is to inhibit bone resorption, secondarily bone formation is also inhibited, and in patients with CKD bisphosphonate use often leads to adynamic bone. In some experimental models in animals, the bisphosphonates can inhibit vascular calcification but this effect has not been seen in humans. Intravenous bisphosphonates may cause renal damage but oral doses do not reduce creatinine clearance. In stage 3 CKD, in patients who still have normal PTH, calcium, and alkaline phosphatase, randomized trials show similar benefits as in patients without CKD. Data from stage 4 and 5 CKD are very limited and no clear benefit has been shown.

Ethnic differences in bone and mineral metabolism in healthy people and patients with CKD.

Several studies have shown racial differences in the regulation of mineral metabolism, in the acquisition of bone mass and structure of individuals. In this review, we examine ethnic differences in bone and mineral metabolism in normal individuals and in patients with chronic kidney disease. Black individuals have lower urinary excretion and increased intestinal calcium absorption, reduced levels of 25(OH)D, and high levels of 1.25(OH)2D and parathyroid hormone (PTH). Body phosphorus concentration is higher and the levels of FGF-23 are lower than in whites. Mineral density and bone architecture are better in black individuals. These differences translate into advantages for blacks who have stronger bones, less risk of fractures, and less cardiovascular calcification. In the United States of America, the prevalence of kidney disease is similar in different ethnic groups. However, black individuals progress more quickly to advanced stages of kidney disease than whites. This faster progression does not translate into increased mortality, higher in whites, especially in the first year of dialysis. Some ethnicity-related variations in mineral metabolism persist when individuals develop CKD. Therefore, black patients have lower serum calcium concentrations, less hyperphosphatemia, low levels of 25(OH)D, higher levels of PTH, and low levels of FGF-23 compared with white patients. Bone biopsy studies show that blacks have greater bone volume. The rate of fractures and cardiovascular diseases are also less frequent. Further studies are required to better understand the cellular and molecular bases of these racial differences in bone mineral metabolism and thus better treat patients.