Serum Phosphate Is Associated With Fracture Risk: The Rotterdam Study and MrOS

Abstract

Extreme phosphate levels (P) have been associated with mineralization defects and increased fracture risk. Whether P within normal range is related to bone health in the general population is not well understood. To investigate the association of P with bone mineral density (BMD) and fracture risk, we assessed two population-based cohorts: the Dutch Rotterdam Study (RS-I, RS-II, RS-III; n=6791) and the US Osteoporotic Fractures in Men (MrOS; n=5425) study. The relationship of P with lumbar spine (LS) and femoral neck (FN) BMD was tested in all cohorts via linear models; fracture risk was tested in RS-I, RS-II and MrOS through Cox models, after follow-up of 8.6, 6.6 and 10.9 years, respectively. Adjustments were made for age, body mass index, smoking, serum levels of calcium, potassium, 25-hydroxyvitamin D, and estimated glomerular filtration rate (eGFR), FN-BMD, prevalent diabetes and cardiovascular disease. Additional adjustments were made for phosphate intake, parathyroid hormone, and fibroblast growth factor 23 levels in MrOS. We further stratified by eGFR. Results were pooled through study-level meta-analyses. Hazard ratios (HR) and betas (β) (from meta-analyses) are expressed per 1 mg/dL P increase. P was positively associated with fracture risk in men and women from RS and findings were replicated in MrOS (pooled HR all (95% CI): 1.47 (1.31–1.65)). P was associated with fracture risk in subjects without chronic kidney disease (CKD): all (1.44 (1.26–1.63)) and in men with CKD (1.93 (1.42–2.62)). P was inversely related to LS-BMD in men (β: −0.06 (−0.11 to −0.02)) and not to FN-BMD in either sex. In summary, serum P was positively related to fracture risk independently from BMD and phosphate intake after adjustments for potential confounders. P and LS-BMD were negatively related in men. Our findings suggest that increased P levels even within normal range might be deleterious for bone health in the normal population.

Fractures in patients with CKD—diagnosis, treatment, and prevention: a review by members of the European Calcified Tissue Society and the European Renal Association of Nephrology Dialysis and Transplantation

“…In population-based cohorts, serum phosphate levels are positively associated with fracture risk in both sexes and in a subgroup of men with CKD. 107 This was maintained after adjustment for FGF23 and PTH, which indicates that high phosphate itself and not underlying hormonal disturbances may explain the high fracture risk. Reduced bone mass and increased fracture risk associated with hyperphosphatemia could be mediated by a lower osteoblastic proliferation through insulin growth factor 1 and osteopontin gene expression.…”

Effects of Excessive Dietary Phosphorus Intake on Bone Health

“…Additionally, accurate assessment of dietary phosphorus intake from food frequency questionnaires is limited by participant errors as well as incomplete and inaccurate nutrient database content (15). Campos-Obando et al (53) also note that the increased fracture risk associated with serum phosphate was observed within the normal range for serum phosphate, which may suggest that usual intakes are too high. However, whether dietary phosphorus intake affects serum phosphate levels within the normal range remains unclear.…”

“…In contrast, in a Brazilian cohort with low average calcium intake (~400 mg/d), for each increase of 100 mg/d in dietary phosphorus there was a 9% increase in fracture risk (52). Recently, a combined analysis of the relationship between serum phosphate and fracture risk in the Rotterdam Study and MrOS prospective cohorts was reported by Campos-Obando et al (53). Serum phosphate was positively related to fracture risk, where there was a 47% increased risk of fracture with each 1 mg/dL increase in serum phosphate after adjusting for multiple covariates.…”

The physiology of endocrine systems with ageing

“…A previous study showed that older men and women, even without overt kidney disease, have an increased fracture risk with increasing serum phosphate concentrations, even when these are within the normal range, and independently of bone mineral density. 92 Whether this increased fracture risk is directly related to serum phosphate concentration or to underlying changes in phosphate-regulating hormones, such as osteocyte-derived FGF23, α-Klotho, parathyroid hormone, or 1,25-hydroxyvitamin D, remains unknown. FGF23 is a hormone secreted by osteocytes in the bone, which together with its co-factor α-Klotho inhibits phosphate reabsorption and 1,25-hydroxyvitamin D production in the kidney.…”