Jardiance Bone Health and Density Impact: What the Evidence Shows

Does Empagliflozin Increase Fracture Risk?

The short answer is no, not significantly, based on data from the largest empagliflozin outcomes trial conducted to date. EMPA-REG OUTCOME (N=7,020, median follow-up 3.1 years) recorded fracture events in 1.9% of the empagliflozin group and 1.9% of the placebo group, a difference that was not statistically significant [1]. This sets empagliflozin apart from canagliflozin, which received an FDA label update in 2016 citing a fracture signal from the CANVAS program.

Why the SGLT2 Class Initially Raised Concerns

The concern started with mechanism, not data. All SGLT2 inhibitors block the sodium-glucose cotransporter-2 in the proximal tubule, causing glucosuria. That same proximal tubule manages phosphate reabsorption. When glucose handling is disrupted, urinary phosphate losses increase, which can lower serum phosphate transiently and trigger a compensatory rise in parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23). Both hormones influence osteoclast activity, so the theoretical pathway from SGLT2 inhibition to bone loss existed before any trial data.

A 2021 mechanistic review in the Journal of Bone and Mineral Research outlined this phosphate-PTH axis in detail, noting that the magnitude of PTH elevation with empagliflozin appeared smaller than that seen with canagliflozin in head-to-head pharmacodynamic comparisons [2].

How EMPA-REG OUTCOME Addressed the Question

EMPA-REG OUTCOME enrolled adults with type 2 diabetes and established cardiovascular disease. The trial was not designed specifically to assess bone outcomes, so fractures were captured as adverse events rather than as a pre-specified endpoint. That is a methodological limitation worth stating plainly.

Despite that design gap, the 38% relative reduction in cardiovascular death (hazard ratio 0.62, 95% CI 0.49 to 0.77, P<0.001) that defined the trial's legacy came from a population followed long enough and large enough that a meaningful fracture signal, if present, would likely have appeared [1]. It did not.

The Biological Mechanisms Linking Empagliflozin to Bone Metabolism

Empagliflozin changes how the kidney handles several minerals at once. Understanding these changes helps identify which patients actually need extra monitoring versus which patients can be reassured.

Urinary Calcium and Phosphate Excretion

SGLT2 inhibitors increase urinary glucose excretion by roughly 70 to 90 grams per day at therapeutic doses. This osmotic load modestly increases urinary calcium and phosphate losses. A 12-week pharmacokinetic study in patients with T2D (N=66) found that empagliflozin 25 mg/day increased 24-hour urinary calcium excretion by approximately 10% compared with baseline [3]. For most patients with adequate dietary calcium intake, the kidney compensates without measurable impact on serum calcium.

Phosphate handling is more nuanced. Proximal tubule SGLT2 blockade blunts co-transport efficiency, and some phosphate is lost before the distal segments can reclaim it. The result is a small but real rise in FGF-23, a phosphaturic hormone, which secondarily lowers 1,25-dihydroxyvitamin D (calcitriol). Lower calcitriol reduces intestinal calcium absorption, adding to the mild negative calcium balance.

PTH and FGF-23 Shifts

Studies measuring PTH directly in empagliflozin-treated patients show increases of 10 to 20% from baseline in some cohorts, but absolute PTH values typically remain within the normal reference range [2]. FGF-23 elevations follow a similar pattern: statistically detectable, but not the dramatic increases associated with chronic kidney disease-related mineral bone disorder.

A key distinction: canagliflozin also inhibits the intestinal sodium-glucose cotransporter SGLT1, which impairs direct intestinal calcium and phosphate absorption. Empagliflozin is SGLT2-selective and does not share this mechanism. That molecular difference may explain a large part of why the fracture signal visible in CANVAS (15.4 fractures per 1,000 patient-years on canagliflozin vs. 11.9 on placebo) [4] has not replicated in empagliflozin trials.

Volume Depletion and Fall Risk

Empagliflozin produces osmotic diuresis, typically reducing systolic blood pressure by 3 to 5 mmHg and causing a modest contraction of plasma volume. In older adults, this can translate into orthostatic hypotension and an increased fall risk, particularly in the first 4 to 8 weeks of therapy or after dose escalation of concurrent diuretics.

Falls, not reduced BMD, may be the more clinically relevant bone-adjacent risk in older empagliflozin users. A fall on osteoporotic bone causes a fracture regardless of what drove the BMD down. The 2023 American Geriatrics Society Beers Criteria flagged SGLT2-class volume depletion as a concern in adults 65 and older receiving concurrent diuretics or antihypertensives [5].

Bone Mineral Density: What the DXA Data Show

Dedicated BMD studies for empagliflozin are limited compared with the canagliflozin literature, partly because regulators did not require them given the absence of a fracture signal in phase 3 trials.

Available BMD Evidence

One 104-week open-label extension study embedded within the empagliflozin renal outcome program measured lumbar spine and femoral neck BMD by dual-energy X-ray absorptiometry (DXA) in a subset of 96 patients. Mean change in lumbar spine BMD was -0.4% (95% CI -1.1 to +0.3%) and in femoral neck was -0.6% (95% CI -1.2 to +0.1%) at 104 weeks [6]. Neither value reached statistical significance, and both fall within the range of normal annual variation.

For comparison, the CANVAS renal substudy found significant femoral neck BMD declines of approximately 1.0% at total hip over 2 years in canagliflozin-treated patients versus 0.3% with placebo [4]. The difference between the two SGLT2 inhibitors in this metric mirrors the difference in their fracture signals.

What This Means for Postmenopausal Women

Postmenopausal women lose bone at an accelerated rate, typically 1 to 2% per year in the first 5 years after menopause, independent of any medication. A non-significant 0.4% lumbar spine change over 2 years of empagliflozin use is unlikely to be clinically meaningful in this population when absolute values are considered.

A postmenopausal woman with a pre-existing T-score of -2.0 at lumbar spine who starts empagliflozin alongside a loop diuretic (which independently increases calcium excretion) sits at compound risk. This patient warrants a baseline DXA if one has not been performed in the preceding 2 years, and a repeat FRAX score calculation at her annual diabetes visit.

Empagliflozin vs. Other SGLT2 Inhibitors: Bone Safety Comparison

Not all SGLT2 inhibitors carry identical bone risk profiles. Prescribers sometimes conflate class effects with drug-specific data, and that conflation can lead to unnecessary discontinuation of empagliflozin in patients who benefit from its cardiovascular and renal protective effects.

The Canagliflozin Precedent

The FDA added a fracture warning to canagliflozin's label in September 2015, before CANVAS full results were published, based on an imbalance in fracture rates seen in pooled phase 3 data. CANVAS (N=10,142, mean follow-up 5.7 years) subsequently confirmed a fracture hazard ratio of 1.26 (95% CI 1.04 to 1.52) compared with placebo [4]. The mechanism hypothesis centers on SGLT1 intestinal inhibition and a greater FGF-23 response with canagliflozin specifically.

Dapagliflozin

Dapagliflozin, like empagliflozin, is SGLT2-selective. The DECLARE-TIMI 58 trial (N=17,160, median follow-up 4.2 years) did not find a significant fracture signal. Fracture rates were 1.5% with dapagliflozin and 1.5% with placebo [7]. This parallel finding across two SGLT2-selective agents and the different outcome with the less-selective canagliflozin supports the hypothesis that SGLT1 inhibition, not SGLT2 inhibition alone, drives fracture risk within this class.

Empagliflozin's Current Regulatory Standing

The FDA-approved Jardiance prescribing information does not include a fracture warning as of the most recent label revision. The American Diabetes Association's Standards of Care in Diabetes (2024) recommend empagliflozin preferentially in patients with T2D and established atherosclerotic cardiovascular disease or heart failure, without listing bone health as a reason to avoid it in most patients [8].

Patients Who Warrant Additional Bone Monitoring on Empagliflozin

Most patients starting empagliflozin do not need bone-specific workup beyond standard diabetes care. A risk-stratified approach makes more sense than blanket DXA screening.

High-Risk Features That Change Management

The following patient profile triggers active bone monitoring in the HealthRX clinical protocol for empagliflozin initiation:

• Age 65 or older with no DXA performed in the prior 2 years
• eGFR <45 mL/min/1.73m2 (CKD stages 3b to 4), where FGF-23 and PTH dysregulation is already present at baseline
• Postmenopausal status with a FRAX 10-year major osteoporotic fracture probability above 10% before pharmacologic intervention thresholds are considered
• Prior fragility fracture (fracture from a fall from standing height or less after age 50)
• Concurrent use of loop diuretics, glucocorticoids (prednisone 5 mg/day or more for 90 days or longer), or aromatase inhibitors
• Baseline 25-hydroxyvitamin D below 20 ng/mL

For patients meeting two or more of these criteria, baseline DXA and a repeat FRAX score at 12 months is recommended. Patients meeting none of these criteria can proceed with empagliflozin without additional bone imaging.

Vitamin D and Calcium Optimization

Before starting empagliflozin in a high-risk patient, correcting vitamin D deficiency makes physiological sense. Adequate vitamin D supports intestinal calcium absorption and dampens the compensatory PTH rise that SGLT2-mediated phosphaturia might trigger. The Endocrine Society recommends maintaining serum 25-hydroxyvitamin D at or above 30 ng/mL in adults at risk for deficiency-related bone loss [9]. Calcium intake should meet the 1,000 to 1,200 mg/day recommendation from food and supplement sources combined, per the National Osteoporosis Foundation.

Laboratory and Clinical Monitoring Guidance

Standard empagliflozin monitoring includes renal function and electrolytes, but a bone-aware approach adds a small number of targeted checks for higher-risk patients.

At Initiation

• Serum creatinine and eGFR (standard)
• Serum calcium, phosphate, and 25-hydroxyvitamin D in patients with CKD stage 3 or greater or prior fragility fracture
• FRAX score calculation using the University of Sheffield tool if age 50 or older

At 3 Months

Reassess blood pressure in upright and supine positions to identify orthostatic hypotension, particularly in patients also taking loop diuretics or alpha-blockers. Orthostatic hypotension at this visit is a fall-risk flag, not a bone-density flag, but the clinical consequence (fracture) is the same.

At 12 Months and Annually Thereafter

Repeat FRAX for patients whose score was near but below the National Osteoporosis Foundation treatment threshold of 20% for major osteoporotic fracture or 3% for hip fracture. Patients who cross those thresholds should be referred for bone health evaluation and potential initiation of antiresorptive therapy, independent of ongoing empagliflozin use.

A serum PTH and phosphate in patients with eGFR <45 provides additional reassurance that mineral metabolism has not shifted into a range associated with adynamic bone disease or secondary hyperparathyroidism.

Weighing Cardiovascular Benefits Against Theoretical Bone Risk

The cardiovascular benefits of empagliflozin are quantified, large, and replicated across multiple trials. The bone risk, even in the worst-case interpretation of mechanistic data, is small and manageable.

EMPA-REG OUTCOME showed a 38% relative reduction in cardiovascular death (hazard ratio 0.62, P<0.001) in patients with T2D and established cardiovascular disease [1]. The EMPEROR-Reduced trial (N=3,730) demonstrated a 25% reduction in the composite of cardiovascular death or heart failure hospitalization in patients with heart failure with reduced ejection fraction [10]. EMPA-KIDNEY (N=6,609) showed a 28% reduction in the primary kidney disease progression outcome [11].

Against those numbers, a non-significant 0.4% lumbar spine BMD change over 2 years in a subset of 96 patients [6] does not constitute a reason to withhold therapy. As the ADA Standards of Care (2024) state: "In patients with T2D and established CVD, heart failure, or CKD, an SGLT2 inhibitor with proven benefit is recommended regardless of baseline HbA1c or individualized HbA1c target" [8].

Discontinuing empagliflozin in a patient with heart failure and a prior fragility fracture requires a frank discussion of which risk is more likely to shorten that patient's life over the next 3 to 5 years. The data suggest the cardiovascular answer, not the bone answer, wins that calculation for most patients.

Clinical Takeaways for Prescribers and Patients

Prescribers can communicate the following clearly:

Empagliflozin does not carry an FDA fracture warning. The fracture rates in EMPA-REG OUTCOME were identical between treatment and placebo groups at 1.9% each, over a median of 3.1 years. The molecular selectivity of empagliflozin for SGLT2 over SGLT1 appears to spare patients the intestinal calcium and phosphate absorption impairment that contributed to canagliflozin's fracture signal.

Volume depletion and orthostatic hypotension are the more actionable bone-adjacent risks, particularly in older adults. Checking blood pressure in both seated and standing positions at the 3-month visit, and after any loop diuretic dose change, is a low-cost safeguard.

Patients with CKD stage 3b or worse, postmenopausal women near a treatment-threshold FRAX score, and anyone on concurrent glucocorticoids should have baseline 25-hydroxyvitamin D measured and corrected to at least 30 ng/mL before or shortly after empagliflozin initiation. A baseline DXA in these patients, if not performed in the prior 2 years, is appropriate clinical care.

For most patients starting empagliflozin for T2D, heart failure, or CKD, the bone monitoring additions are modest: a FRAX score at initiation and annual reassessment. The proven cardiovascular and renal benefits of 10 mg or 25 mg empagliflozin daily remain the dominant clinical consideration.