Fracture Risk Among Living Kidney Donors 25 Years After Donation.

Importance: Living kidney donors may have an increased risk of fractures due to reductions in kidney mass, lower concentrations of serum 1,25-dihydroxyvitamin D, and secondary increases in serum parathyroid hormone. Objective: To compare the overall and site-specific risk of fractures among living kidney donors with strictly matched controls from the general population who would have been eligible to donate a kidney but did not do so. Design, Setting, and Participants: This survey study was conducted between December 1, 2021, and July 31, 2023. A total of 5065 living kidney donors from 3 large transplant centers in Minnesota were invited to complete a survey about their bone health and history of fractures, and 16 156 population-based nondonor controls without a history of comorbidities that would have precluded kidney donation were identified from the Rochester Epidemiology Project and completed the same survey. A total of 2132 living kidney donors and 2014 nondonor controls responded to the survey. Statistical analyses were performed from May to August 2023. Exposure: Living kidney donation. Main Outcomes and Measures: The rates of overall and site-specific fractures were compared between living kidney donors and controls using standardized incidence ratios (SIRs). Results: At the time of survey, the 2132 living kidney donors had a mean (SD) age of 67.1 (8.9) years and included 1245 women (58.4%), and the 2014 controls had a mean (SD) age of 68.6 (7.9) years and included 1140 women (56.6%). The mean (SD) time between donation or index date and survey date was 24.2 (10.4) years for donors and 27.6 (10.7) years for controls. The overall rate of fractures among living kidney donors was significantly lower than among controls (SIR, 0.89; 95% CI, 0.81-0.97). However, there were significantly more vertebral fractures among living kidney donors than among controls (SIR, 1.42; 95% CI, 1.05-1.83). Conclusions and Relevance: This survey study found a reduced rate of overall fractures but an excess of vertebral fractures among living kidney donors compared with controls after a mean follow-up of 25 years. Treatment of excess vertebral fractures with dietary supplements such as vitamin D3 may reduce the numbers of vertebral fractures and patient morbidity.

Secondary Fracture Prevention: Consensus Clinical Recommendations from a Multistakeholder Coalition.

Osteoporosis-related fractures are undertreated, due in part to misinformation about recommended approaches to patient care and discrepancies among treatment guidelines. To help bridge this gap and improve patient outcomes, the American Society for Bone and Mineral Research assembled a multistakeholder coalition to develop clinical recommendations for the optimal prevention of secondary fractureamong people aged 65 years and older with a hip or vertebral fracture. The coalition developed 13 recommendations (7 primary and 6 secondary) strongly supported by the empirical literature. The coalition recommends increased communication with patients regarding fracture risk, mortality and morbidity outcomes, and fracture risk reduction. Risk assessment (including fall history) should occur at regular intervals with referral to physical and/or occupational therapy as appropriate. Oral, intravenous, andsubcutaneous pharmacotherapies are efficaciousandcanreduce risk of future fracture.Patientsneededucation,however, about thebenefitsandrisks of both treatment and not receiving treatment. Oral bisphosphonates alendronate and risedronate are first-line options and are generally well tolerated; otherwise, intravenous zoledronic acid and subcutaneous denosumab can be considered. Anabolic agents are expensive butmay be beneficial for selected patients at high risk.Optimal duration of pharmacotherapy is unknown but because the risk for second fractures is highest in the earlypost-fractureperiod,prompt treatment is recommended.Adequate dietary or supplemental vitaminDand calciumintake shouldbe assured. Individuals beingtreatedfor osteoporosis shouldbe reevaluated for fracture risk routinely, includingvia patienteducationabout osteoporosisandfracturesandmonitoringfor adverse treatment effects.Patients shouldbestronglyencouraged to avoid tobacco, consume alcohol inmoderation atmost, and engage in regular exercise and fall prevention strategies. Finally, referral to endocrinologists or other osteoporosis specialists may be warranted for individuals who experience repeated fracture or bone loss and those with complicating comorbidities (eg, hyperparathyroidism, chronic kidney disease).

Secondary Fracture Prevention: Consensus Clinical Recommendations from a Multistakeholder Coalition.

Osteoporosis-related fractures are undertreated, due in part to misinformation about recommended approaches to patient care and discrepancies among treatment guidelines. To help bridge this gap and improve patient outcomes, the American Society for Bone and Mineral Research assembled a multistakeholder coalition to develop clinical recommendations for the optimal prevention of secondary fracture among people aged 65 years and older with a hip or vertebral fracture. The coalition developed 13 recommendations (7 primary and 6 secondary) strongly supported by the empirical literature. The coalition recommends increased communication with patients regarding fracture risk, mortality and morbidity outcomes, and fracture risk reduction. Risk assessment (including fall history) should occur at regular intervals with referral to physical and/or occupational therapy as appropriate. Oral, intravenous, and subcutaneous pharmacotherapies are efficacious and can reduce risk of future fracture. Patients need education, however, about the benefits and risks of both treatment and not receiving treatment. Oral bisphosphonates alendronate and risedronate are first-line options and are generally well tolerated; otherwise, intravenous zoledronic acid and subcutaneous denosumab can be considered. Anabolic agents are expensive but may be beneficial for selected patients at high risk. Optimal duration of pharmacotherapy is unknown but because the risk for second fractures is highest in the early post-fracture period, prompt treatment is recommended. Adequate dietary or supplemental vitamin D and calcium intake should be assured. Individuals being treated for osteoporosis should be reevaluated for fracture risk routinely, including via patient education about osteoporosis and fractures and monitoring for adverse treatment effects. Patients should be strongly encouraged to avoid tobacco, consume alcohol in moderation at most, and engage in regular exercise and fall prevention strategies. Finally, referral to endocrinologists or other osteoporosis specialists may be warranted for individuals who experience repeated fracture or bone loss and those with complicating comorbidities (eg, hyperparathyroidism, chronic kidney disease). © 2019 American Society for Bone and Mineral Research.

A Lot of Progress, With More to Be Done: A Response to NIH Pathways to Prevention Report "Research Gaps for Long-Term Drug Therapies for Osteoporotic Fracture Prevention".

The public health implications of osteoporosis are enormous but the disease remains underdiagnosed and undertreated. In October 2018, the National Institutes of Health (NIH) convened a Pathways to Prevention (P2P) Workshop entitled "Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention" designed to identify research gaps, suggest future research opportunities, and advance the field through an evidence-based assessment. By design, the P2P report focused on "gaps" in our knowledge base. Unfortunately, however, the report did not sufficiently acknowledge the current evidence that unequivocally demonstrates the therapeutic efficacy of existing pharmacologic therapies for osteoporosis, which has the potential to exacerbate the current crises in osteoporosis diagnosis and treatment. © 2019 American Society for Bone and Mineral Research.

Effects of adjuvant exemestane versus anastrozole on bone mineral density for women with early breast cancer (MA.27B): a companion analysis of a randomised controlled trial.

BACKGROUND: Treatment of breast cancer with aromatase inhibitors is associated with damage to bones. NCIC CTG MA.27 was an open-label, phase 3, randomised controlled trial in which women with breast cancer were assigned to one of two adjuvant oral aromatase inhibitors-exemestane or anastrozole. We postulated that exemestane-a mildly androgenic steroid-might have a less detrimental effect on bone than non-steroidal anastrozole. In this companion study to MA.27, we compared changes in bone mineral density (BMD) in the lumbar spine and total hip between patients treated with exemestane and patients treated with anastrozole. METHODS: In MA.27, postmenopausal women with early stage hormone (oestrogen) receptor-positive invasive breast cancer were randomly assigned to exemestane 25 mg versus anastrozole 1 mg, daily. MA.27B recruited two groups of women from MA.27: those with BMD T-scores of -2·0 or more (up to 2 SDs below sex-matched, young adult mean) and those with at least one T-score (hip or spine) less than -2·0. Both groups received vitamin D and calcium; those with baseline T-scores of less than -2·0 also received bisphosphonates. The primary endpoints were percent change of BMD at 2 years in lumbar spine and total hip for both groups. We analysed patients according to which aromatase inhibitor and T-score groups they were allocated to but BMD assessments ceased if patients deviated from protocol. This study is registered with ClinicalTrials.gov, NCT00354302. FINDINGS: Between April 24, 2006, and May 30, 2008, 300 patients with baseline T-scores of -2·0 or more were accrued (147 allocated exemestane, 153 anastrozole); and 197 patients with baseline T-scores of less than -2·0 (101 exemestane, 96 anastrozole). For patients with T-scores greater than -2·0 at baseline, mean change of bone mineral density in the spine at 2 years did not differ significantly between patients taking exemestane and patients taking anastrozole (-0·92%, 95% CI -2·35 to 0·50 vs -2·39%, 95% CI -3·77 to -1·01; p=0·08). Respective mean loss in the hip was -1·93% (95% CI -2·93 to -0·93) versus -2·71% (95% CI -4·32 to -1·11; p=0·10). Likewise for those who started with T-scores of less than -2·0, mean change of spine bone mineral density at 2 years did not differ significantly between the exemestane and anastrozole treatment groups (2·11%, 95% CI -0·84 to 5·06 vs 3·72%, 95% CI 1·54 to 5·89; p=0·26), nor did hip bone mineral density (2·09%, 95% CI -1·45 to 5·63 vs 0·0%, 95% CI -3·67 to 3·66; p=0·28). Patients with baseline T-score of -2·0 or more taking exemestane had two fragility fractures and two other fractures, those taking anastrozole had three fragility fractures and five other fractures. For patients who had baseline T-scores of less than -2·0 taking exemestane, one had a fragility fracture and four had other fractures, whereas those taking anastrozole had five fragility fractures and one other fracture. INTERPRETATION: Our results demonstrate that adjuvant treatment with aromatase inhibitors can be considered for breast cancer patients who have T-scores less than -2·0. FUNDING: Canadian Cancer Society Research Institute, Pfizer, Canadian Institutes of Health Research.

Polyphenol-rich cranberry juice has a neutral effect on endothelial function but decreases the fraction of osteocalcin-expressing endothelial progenitor cells.

PURPOSE: Cranberry juice (CJ) contains a remarkably high concentration of polyphenols, considered to be beneficial for cardiovascular and bone health. The current double-blind, randomized study was designed to test whether daily consumption of double-strength Ocean Spray light CJ (2 × 230 ml) over 4 months has beneficial effects on vascular function and on endothelial progenitor cells (EPCs) carrying the osteoblastic marker osteocalcin in particular. METHODS: A total of 84 participants (49.5 ± 16.2 years) with peripheral endothelial dysfunction and cardiovascular risk factors were enrolled in this double-blind, randomized, controlled trial (69 completed the 4-month protocol-32 in the CJ group and 37 in the placebo group, respectively). Vascular responses to reactive hyperemia were measured non-invasively by peripheral arterial tonometry (EndoPAT). Peripheral blood mononuclear cells were stained for EPC markers, as well as osteocalcin, and counted by flow cytometry. RESULTS: Baseline characteristics were similar in both groups. The effect of CJ on peripheral endothelial function and on circulating EPC counts (CD34(+)/CD133(+)/KDR(+)) did not change during the study. A high percentage of EPCs expressed osteocalcin (59.4 ± 35.7%). CJ, as compared to placebo, induced a decrease in the fraction of EPCs expressing osteocalcin (-8.64 ± 48.98 and 19.13 ± 46.11%, respectively, p = 0.019). Systemic levels of the adhesion marker ICAM correlated significantly with the number of EPCs expressing osteocalcin. CONCLUSIONS: The study demonstrated that long-term supplementation of polyphenol-rich CJ did not improve peripheral endothelial function. However, the decrease in the fraction of osteocalcin+ EPCs suggests a potential beneficial effect of polyphenol-rich CJ.

Effects of bisphosphonate treatment on circulating osteogenic endothelial progenitor cells in postmenopausal women.

OBJECTIVE: To evaluate whether bisphosphonates modulate vascular calcification by a modification in endothelial progenitor cells (EPCs) coexpressing osteoblastic surface markers and genes. PATIENTS AND METHODS: We performed a double-blind, randomized study of 20 healthy, early postmenopausal women (from February 1, 2008, through July 31, 2008) treated with placebo or risedronate sodium (35 mg/wk) for 4 months. Peripheral blood was collected at baseline and 4 months to determine serum inflammatory markers, osteoprotegerin, and receptor activator of nuclear factor-κB ligand levels and bone turnover markers. Peripheral blood mononuclear cells were stained for EPC surface markers (CD34, CD133, and vascular endothelial growth factor receptor/kinase insert domain receptor) and osteoblast markers (osteocalcin, alkaline phosphatase, and Stro-1). RESULTS: Risedronate treatment resulted in a significant down-regulation of gene sets for osteoblast differentiation and proliferation in EPCs with a trend of decreasing EPCs coexpressing osteocalcin. CONCLUSION: Our findings indicate that bisphosphonate treatment down-regulates the expression of osteogenic genes in EPCs and suggest a possible mechanism by which bisphosphonates may inhibit vascular calcification.

Bone density and structure in healthy postmenopausal women treated with exemestane for the primary prevention of breast cancer: a nested substudy of the MAP.3 randomised controlled trial.

BACKGROUND: Exemestane can prevent breast cancer in postmenopausal women. Because of potential widespread use, we examined the safety of exemestane on bone health. METHODS: In this nested safety substudy of the MAP.3 trial (a randomised, placebo-controlled, double-blind trial of exemestane 25 mg a day for the primary prevention of breast cancer), we included postmenopausal women from five centres who were eligible to participate in MAP.3, not osteoporotic, not receiving drugs for bone-related disorders, with baseline lumbar spine, total hip, and femoral neck T-scores above -2·0. The primary endpoint was percent change from baseline to 2 years in total volumetric bone mineral density (BMD) at the distal radius by high-resolution peripheral quantitative CT. The primary analysis was per protocol using a non-inferiority margin. This analysis was done earlier than originally planned because of the impending announcement of MAP.3 results and subsequent unmasking of patients to treatment assignment. This study is registered with ClinicalTrials.gov, number NCT01144468, and has been extended to 5 years of unmasked follow-up. FINDINGS: 351 women (176 given exemestane, 175 given placebo; median age 61·3 years [IQR 59·2-64·9]) met our inclusion criteria and completed baseline assessment. At the time of clinical cutoff, 242 women had completed 2-year follow-up (124 given exemestane, 118 given placebo). From baseline to 2 years, the mean percent change in total volumetric BMD at the distal radius was -6·1% (95% CI -7·0 to -5·2) in the exemestane group and -1·8% (-2·4 to -1·2) in the placebo group (difference -4·3%, 95% CI -5·3 to -3·2; p<0·0001). The lower limit of the 95% CI was lower than our non-inferiority margin of negative 4% (one-sided test for non-inferiority p=0·70), meaning the hypothesis that exemestane was inferior could not be rejected. At the distal tibia, the mean percent change in total volumetric BMD from baseline to 2 years was -5·0% (95% CI -5·5 to -4·4) in the exemestane group and -1·3% (-1·7 to -1·0) in the placebo group (difference -3·7%, 95% CI -4·3 to -3·0; p<0·0001). The mean percent change in cortical thickness was -7·9% (SD 7·3) in the exemestane group and -1·1% (5·7) in the placebo group at the distal radius (difference -6·8%, 95% CI -8·5 to -5·0; p<0·0001) and -7·6% (SD 5·9) in the exemestane group and -0·7% (4·9) in the placebo group at the distal tibia (difference -6·9%, -8·4 to -5·5; p<0·0001). Decline in areal BMD, as measured by dual-energy x-ray absorptiometry, in the exemestane group compared with the placebo group occurred at the lumbar spine (-2·4% [95% CI -3·1 to -1·7] exemestane vs -0·5% [-1·1 to 0·2] placebo; difference -1·9%, 95% CI -2·9 to -1·0; p<0·0001), total hip (-1·8% [-2·3 to -1·2] exemestane vs -0·6% [-1·1 to -0·1] placebo; difference -1·2%, -1·9 to -0·4; p=0·004), and femoral neck (-2·4% [-3·2 to -1·7] exemestane vs -0·8% [-1·5 to 0·1] placebo; difference -1·6%, -2·7 to -0·6; p=0·002). INTERPRETATION: 2 years of treatment with exemestane worsens age-related bone loss in postmenopausal women despite calcium and vitamin D supplementation. Women considering exemestane for the primary prevention of breast cancer should weigh their individual risks and benefits. For women taking exemestane, regular bone monitoring plus adequate calcium and vitamin D supplementation are important. To assess the effect of our findings on fracture risk, long-term follow-up is needed. FUNDING: Canadian Breast Cancer Research Alliance (Canadian Institutes of Health Research/Canadian Cancer Society).

Effects of physiological variations in circulating insulin levels on bone turnover in humans.

CONTEXT: Recent studies in mice have demonstrated that insulin signaling in osteoblasts stimulates bone formation and reduces osteoprotegerin production; the latter results in an increase in bone resorption, which then leads to the release of undercarboxylated osteocalcin from bone. Undercarboxylated osteocalcin, in turn, enhances insulin sensitivity. OBJECTIVE: The objective of the study was to test whether physiological changes in insulin levels regulate bone metabolism in humans. DESIGN: This investigation was an analysis of samples from a prospective study. SETTING: The study was conducted at a clinical research unit. PARTICIPANTS AND INTERVENTIONS: Fourteen subjects underwent a 7-h stepped insulin infusion accompanied by a glucose clamp and somatostatin infusion along with replacement infusions of GH and glucagon, thus isolating possible effects of insulin on bone. Insulin was infused at rates achieving low (∼150 pmol/liter), intermediate (∼350 pmol/liter), or high (∼700 pmol/liter) plasma insulin levels. MAIN OUTCOME MEASURES: Bone turnover markers, undercarboxylated osteocalcin, and osteoprotegerin levels at the end of the low, intermediate, and high dose insulin infusions were measured. RESULTS: Values for the outcome measures at the end of the intermediate- and high-dose insulin infusions were no different from values at the end of the low-dose insulin infusion. However, measures of insulin sensitivity (glucose infusion and disappearance rates) correlated positively with C-terminal telopeptide of type I collagen levels. CONCLUSIONS: Acute changes in insulin levels, as occur during meals, do not regulate bone turnover, undercarboxylated osteocalcin, or osteoprotegerin levels. However, the correlation of measures of insulin sensitivity with bone resorption suggests the need for further studies in humans on the possible regulation of bone metabolism by insulin.

Osteoporosis in men.

With the aging of the population, there is a growing recognition that osteoporosis and fractures in men are a significant public health problem, and both hip and vertebral fractures are associated with increased morbidity and mortality in men. Osteoporosis in men is a heterogeneous clinical entity: whereas most men experience bone loss with aging, some men develop osteoporosis at a relatively young age, often for unexplained reasons (idiopathic osteoporosis). Declining sex steroid levels and other hormonal changes likely contribute to age-related bone loss, as do impairments in osteoblast number and/or activity. Secondary causes of osteoporosis also play a significant role in pathogenesis. Although there is ongoing controversy regarding whether osteoporosis in men should be diagnosed based on female- or male-specific reference ranges (because some evidence indicates that the risk of fracture is similar in women and men for a given level of bone mineral density), a diagnosis of osteoporosis in men is generally made based on male-specific reference ranges. Treatment consists both of nonpharmacological (lifestyle factors, calcium and vitamin D supplementation) and pharmacological (most commonly bisphosphonates or PTH) approaches, with efficacy similar to that seen in women. Increasing awareness of osteoporosis in men among physicians and the lay public is critical for the prevention of fractures in our aging male population.

Two years of treatment with dehydroepiandrosterone does not improve insulin secretion, insulin action, or postprandial glucose turnover in elderly men or women.

To determine if dehydroepiandrosterone (DHEA) replacement improves insulin secretion, insulin action, and/or postprandial glucose metabolism, 112 elderly subjects with relative DHEA deficiency ingested a labeled mixed meal and underwent a frequently sampled intravenous glucose tolerance test before and after 2 years of either DHEA or placebo. Despite restoring DHEA sulphate concentrations to values observed in young men and women, the changes over time in fasting and postprandial glucose concentrations, meal appearance, glucose disposal, and endogenous glucose production were identical to those observed after 2 years of placebo. The change over time in postmeal and intravenous glucose tolerance test insulin and C-peptide concentrations did not differ in men treated with DHEA or placebo. In contrast, postmeal and intravenous glucose tolerance test change over time in insulin and C-peptide concentrations were greater (P < 0.05) in women after DHEA than after placebo. However, since DHEA tended to decrease insulin action, the change over time in disposition indexes did not differ between DHEA- and placebo-treated women, indicating that the slight increase in insulin secretion was a compensatory response to a slight decrease in insulin action. We conclude that 2 years of replacement of DHEA in elderly men and women does not improve insulin secretion, insulin action, or the pattern of postprandial glucose metabolism.

DHEA in elderly women and DHEA or testosterone in elderly men.

BACKGROUND: Dehydroepiandrosterone (DHEA) and testosterone are widely promoted as antiaging supplements, but the long-term benefits, as compared with potential harm, are unknown. METHODS: We performed a 2-year, placebo-controlled, randomized, double-blind study involving 87 elderly men with low levels of the sulfated form of DHEA and bioavailable testosterone and 57 elderly women with low levels of sulfated DHEA. Among the men, 29 received DHEA, 27 received testosterone, and 31 received placebo. Among the women, 27 received DHEA and 30 received placebo. Outcome measures included physical performance, body composition, bone mineral density (BMD), glucose tolerance, and quality of life. RESULTS: As compared with the change from baseline to 24 months in the placebo group, subjects who received DHEA for 2 years had an increase in plasma levels of sulfated DHEA by a median of 3.4 microg per milliliter (9.2 micromol per liter) in men and by 3.8 microg per milliliter (10.3 micromol per liter) in women. Among men who received testosterone, the level of bioavailable testosterone increased by a median of 30.4 ng per deciliter (1.1 nmol per liter), as compared with the change in the placebo group. A separate analysis of men and women showed no significant effect of DHEA on body-composition measurements. Neither hormone altered the peak volume of oxygen consumed per minute, muscle strength, or insulin sensitivity. Men who received testosterone had a slight increase in fat-free mass, and men in both treatment groups had an increase in BMD at the femoral neck. Women who received DHEA had an increase in BMD at the ultradistal radius. Neither treatment improved the quality of life or had major adverse effects. CONCLUSIONS: Neither DHEA nor low-dose testosterone replacement in elderly people has physiologically relevant beneficial effects on body composition, physical performance, insulin sensitivity, or quality of life. (ClinicalTrials.gov number, NCT00254371 [ClinicalTrials.gov].).

Potential anabolic effects of androgens on bone.

Sex steroid hormones are essential to normal skeletal growth and maintenance throughout life in both men and women. The importance of estrogens to bone health in women becomes obvious at menopause when estrogen deficiency occurs and results in accelerated bone loss. After menopause, estrogen deficiency results in drastic changes in the androgen-estrogen ratio. Thus, the relative importance of androgens after menopause may increase. Androgens also appear to be important for bone health in pre-menopausal women. Evidence from human, animal, and laboratory studies is leading to a better understanding of the effects of androgens on bone in women.

Effect of estrogen replacement therapy on parathyroid hormone secretion in elderly postmenopausal women.

OBJECTIVE: Women undergo two phases of involutional bone loss that have opposing effects on parathyroid hormone (PTH) secretion. During the early phase, the loss of the direct restraining effect of estrogen on bone resorption causes an outflow of skeletal calcium into the extracellular fluid. This causes a compensatory decrease in PTH secretion. In the late phase, loss of extraskeletal effects of estrogen (on intestinal and renal calcium handling) leads to increases in whole body losses of calcium and a compensatory increase in PTH secretion. Moreover, long-term estrogen replacement therapy (ERT) suppresses both basal and stimulated PTH secretion in these women. Whereas the effects of estrogen on PTH secretion have been assumed to be due to its extraskeletal actions, estrogen may also have direct effects on the parathyroid glands. The goal of the present study was to test for these possible direct effects of estrogen on PTH secretion. DESIGN: Basal and ethylenediaminetetraacetic acid (EDTA)-stimulated PTH secretion was assessed in 10 elderly postmenopausal women (mean age, 76.4 years) before and after acute (3 days) estrogen replacement with transdermal estradiol, 0.1 mg/day. In addition, similar studies were performed in 10 age-matched women (mean age, 74.5 years) who had been on long-term ERT. These women were studied before and after 3 days of estrogen withdrawal. RESULTS: Estrogen treatment or withdrawal had no significant effect on either basal or stimulated PTH secretion. CONCLUSIONS: These data provide evidence that, in elderly postmenopausal women, estrogen does not have significant direct effects on PTH secretion and point to the importance of the actions of estrogen on intestinal and renal calcium handling as the major mechanisms for its effects on modulating calcium homeostasis and, indirectly, PTH secretion.