Patients with diabetes mellitus are at increased risk for bone fragility fracture secondary to multiple mechanisms.
Hyperglycemia can induce true dilutional hyponatremia. Hyponatremia is associated with gait instability, osteoporosis, and increased falls and bone fractures, and studies suggest that compromised bone quality with hyponatremia may be independent of plasma osmolality.
Analyses of this research support the hypothesis that hyponatremia is an additional risk factor for osteoporosis and fragility fracture among patients with diabetes mellitus.
JOURNAL OF THE ENDOCRINE SOCIETY
Patients with diabetes mellitus are at increased risk for bone fragility fracture secondary to multiple mechanisms. Hyperglycemia can induce true dilutional hyponatremia.
Hyponatremia is associated with gait instability, osteoporosis, and increased falls and bone fractures, and studies suggest that compromised bone quality with hyponatremia may be independent of plasma osmolality. We performed a case-control study of patients with diabetes mellitus matched by median glycated hemoglobin (HbA1c) to assess whether hyponatremia was associated with increased risk of osteoporosis and/or fragility fracture.
Osteoporosis (n = 823) and fragility fracture (n = 840) cases from the MedStar Health database were matched on age of first HbA1c ≥6.5%, sex, race, median HbA1c over an interval from first HbA1c ≥6.5% to the end of the encounter window, diabetic encounter window length, and type 1 vs type 2 diabetes mellitus with controls without osteoporosis (n = 823) and without fragility fractures (n = 840), respectively.
Clinical variables, including coefficient of glucose variation and hyponatremia (defined as serum Na+ <135 mmol/dL within 30 days of the end of the diabetic window), were included in a multivariate analysis.
Multivariate conditional logistic regression models demonstrated that hyponatremia within 30 days of the outcome measure was independently associated with osteoporosis and fragility fractures (osteoporosis OR = 3.1 p<0.05; fracture OR = 6.4, p<0.05).
Our analyses support the hypothesis that hyponatremia is an additional risk factor for osteoporosis and fragility fracture among patients with diabetes mellitus.
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Low bone mineral density is one predictor of fragility fracture, although most fractures occur in individuals without osteoporosis. Increasingly, it is recognized that having diabetes mellitus is a risk factor for fragility fracture with or without osteoporosis. Incidence of osteoporosis among patients with diabetes mellitus is not uniform and is incompletely understood.
The risk of hip fracture in type 1 diabetes mellitus (T1DM) is significantly higher than is observed in type 2 diabetes mellitus (T2DM), although both are increased relative to risk among the normoglycemic population; and bone mineral density (BMD) is increased in T2DM relative to controls, whereas it is decreased in T1DM.
Despite this heterogeneity of densiometrically identified bone disease among patients with diabetes mellitus, common factors that may contribute to poor bone quality among all diabetic patients include effects of hyperglycemia on osteoblasts, osteoblastic precursors, osteocytes, and osteoclasts; compromise of collagen strength caused by accumulation of advanced glycation end products in bone; oxidative stress from glucose variability; and development of microvascular disease that damages bone vasculature. Furthermore, gait disturbances observed among hyperglycemic patients may be caused by compromised peripheral and central nervous systems, as well as sarcopenia, that collectively contribute to increased risk for falls and fractures.
Similarly, there is evidence that hyponatremia is a risk factor for fragility fracture with or without osteoporosis. Experimental and epidemiological studies associate hyponatremia with increased risk of both osteoporosis and gait instability leading to increased falls and fractures.
Analogous to the release of calcium from bone to maintain calcium homeostasis during calcium deficiency, studies suggest that sodium can be released from rich and mobilizable reservoirs in bone to maintain sodium homeostasis during relative sodium deficiency.
Bone quality could thus be compromised at the expense of attempting to maintain normal serum sodium concentrations [Na+], although the mechanisms affecting this pathophysiology are inadequately understood.
Hyponatremia may compromise bone quality directly and independently of plasma osmolality by activating osteoclast-mediated resorption and loss of bone through direct low-sodium sensing mechanisms, and/or by promoting differentiation of human mesenchymal stromal cells toward the adipogenic phenotype at the expense of osteogenesis. Other studies have suggested that arginine vasopressin (AVP)—the hormone responsible for renal water conservation that is inappropriately elevated in relation to hypo-osmolality with hyponatremia in the syndrome of inappropriate antidiuretic hormone (SIADH)—may be responsible for affecting the release of sodium from bone through interaction with Avpr1α and Avpr2 receptors expressed in osteoblasts and osteoclasts. The mechanisms underlying gait instability associated with hyponatremia are also under active investigation, and they may be caused by central and/or peripheral nervous system dysfunction. Importantly, and in support of the hypothesis that hyponatremia is causative of pathology and not just a marker of disease severity, both the negative effects of hyponatremia on bone quality and gait instability may be reversible.
Our data suggest that, independent of glycemic indices, hyponatremia among persons with diabetes mellitus is associated with increased risk of osteoporosis and fragility fracture. Interestingly, the OR of fracture with hyponatremia (OR, 6.41, p<0.05) was double in magnitude to the OR of osteoporosis with hyponatremia (OR, 3.09, p<0.05). Furthermore, hyponatremia was a greater risk factor for fracture than osteoporosis in our multivariate analysis, suggesting that hyponatremia may incur risk for fracture both by compromising bone quality as measured by densitometry (osteoporosis) and by a second, additive mechanism. This second mechanism likely is gait instability caused by hyponatremia [28, 29] that contributes to increased mechanical falls [30, 31] and fractures [32, 45].
We recognize that the rationale linking pathology associated with hyponatremia to skeletal and nervous system physiology in diabetes mellitus is circumstantial, as investigations to date have not been undertaken with simultaneous consideration of both sodium and glucose levels. Inarguably, hyperglycemia is directly toxic to bone, although there is recent evidence that suggests that there are additional mechanisms independent of absolute glucose level that cause increased bone resorption markers in patients with hyperglycemia. There is also evidence that rapid changes in glucose level (with concomitant rapid changes in absolute serum sodium) can cause toxicity to the nervous system that is similar in character to the pathology seen among patients with rapidly corrected serum sodium levels in hypo-osmolar hyponatremia. As serum [Na+] levels are dependent on glucose levels, the principal challenge of the current study was to demonstrate that hyponatremia among patients with diabetes mellitus could be associated with osteoporosis and fragility fracture independent of the degree of hyperglycemia.
The possibility that patients with diabetes mellitus can have comparable glycemic control but disparate serum [Na+] levels made our case-control study possible. There are three potential mechanisms by which patients with diabetes mellitus could have comparable glycemic control but lower serum [Na+] levels than do their matched controls.
Patients could be both hyperglycemic and have an additional disorder of water homeostasis (such as nonosmotic secretion of AVP caused by a medication) that induces a hypo-osmolar hyponatremia.
Second, some patients could have physiology that depresses serum [Na+] levels lower than would be expected for a given degree of hyperglycemia. Such a phenomenon has been seen in at least one epidemiological study in diabetic patients.
Third, some patients could have low-normal baseline serum [Na+] levels when euglycemic. With the same delta changes in serum glucose and subsequently the same delta changes in serum [Na+] caused by translocation of fluid from the intracellular space to the extracellular space, patients with lower baseline serum [Na+] levels when euglycemic would also have lower serum [Na+] levels when hyperglycemic compared with patients with high baseline serum [Na+] levels.
Although our study design limits our ability to distinguish which of these mechanisms were at play in our study, experimental data do suggest that the third mechanism of isotonic hyponatremia could contribute to increased risk of osteoporosis and fracture, as discussed below.
Frequent hyperglycemia is thought to contribute to increased risk of bone fragility fractures through multiple mechanisms. We introduce the provocative hypothesis that the osmotic property of glucose, which induces dilutional hyponatremia by affecting translocation of water from the intracellular to the extracellular space, may also contribute to the pathophysiology underpinning increased fracture risk among patients with diabetes mellitus. We speculate that hyperglycemia-induced hyponatremia stimulates biologic processes that facilitate release of rich sodium reservoirs from bone to maintain sodium and water homeostasis at the expense of bone quality. Models suggest that impaired nerve conduction and gait stability may be directly related to lowering of [Na+]. Furthermore, hyperglycemia-induced hyponatremia could compound fracture risk by precipitating or worsening gait instability, leading to increased falls and fracture risk.
One strength of the current study is that we controlled for many parameters of hyperglycemia. That is, our cases and controls were matched on a categorization of hyperglycemia etiology (i.e., T1DM vs T2DM), a parameter of hyperglycemia duration (i.e., diabetic window), and a measure of hyperglycemia severity (i.e., median HbA1c). Oxidative stress caused by glucose variability is also proposed as a mechanism of hyperglycemia toxicity, and in a recent study, bone cortical area was inversely associated with glycemic variability as measured by coefficient of glucose variation in patients with T1DM. Recognizing that our matching did not account for glucose variability or glucose excursions, we included coefficient of glucose variation as a variable in our multivariate analysis. Coefficient of glucose variation was not strongly associated with osteoporosis or fracture in the current study, nor did the inclusion of coefficient of glucose variation in the multivariate analysis significantly affect the OR for osteoporosis or fragility fraction with hyponatremia. We do not suggest that our analysis refutes the putative role that glycemic variability contributes to fracture risk; rather, our results suggest that cases and controls were well matched on glycemic parameters and had similar glucose variability.
Another strength of this study is that we control for multiple confounders by including clinical factors associated with risk for osteoporosis and fragility fracture in the multivariate analysis. For example, thiazide diuretic was included in our analysis because it may decrease fracture risk by creating a positive calcium balance or increase fracture risk by causing postural hypotension or hyponatremia. Although hyponatremia was a significant risk factor for osteoporosis and fragility fracture, neither thiazide diuretic nor hypotension was statistically significant for either outcome in our analysis, which suggests that hypotension caused by thiazide diuretic was not a driver for increased risk for fracture in our population.
Although our study is primarily hypothesis generating, there are potential clinical implications that derive from the results. First, they reaffirm that hyperglycemia-induced hyponatremia is a true hyponatremia caused by translocation of water from the intracellular to the extracellular fluid, not an artifactual pseudohyponatremia, which is a frequent misinterpretation. Second, they challenge the prevailing concept that hyperglycemia-induced hyponatremia is of no clinical significance, because hyponatremia was associated with increased risk of osteoporosis and fractures independent of well-matched indices of glycemic control. When matched for glycemic indices, our data suggest that hyponatremia itself is the main driver of osteoporosis and fracture, and the overall effect of glucose on risk for osteoporosis or fragility fracture needs further investigation with controlled trials.