Muscle Loss, Fractures, Osteoporosis, Age Related, Fall Injury
Conditions
Keywords
potassium bicarbonate, urinary N-telopeptide, urinary nitrogen, net acid excretion
Brief summary
With aging, men and women develop a mild and progressive metabolic acidosis. This occurs as a result of declining renal function and ingestion of acid-producing diets. There is extensive evidence that severe metabolic acidosis causes bone and muscle loss, but the impact of the chronic, mild acidosis on bone and muscle in older individuals has not been established. In a recent study, administration of a single dose of bicarbonate daily for 3 months significantly reduced urinary excretion of N-telopeptide (NTX), a marker of bone resorption and urinary nitrogen, a marker of muscle wasting and improved muscle performance in the women but not the men. These and other data support a potential role for bicarbonate as a means of reducing the musculoskeletal declines that lead to extensive morbidity and mortality in the elderly. Before proceeding to a long-term bicarbonate intervention study, however, it is important to identify the dose of bicarbonate most likely to be optimal and to characterize the subjects who benefit most from it. This double blind, placebo controlled, dose-finding study will evaluate the effects of placebo and two doses of bicarbonate on urinary NTX and nitrogen excretion and on lower extremity performance over a 3 month period in 138 men and 138 women, age 60 and older. Changes in urinary excretion of NTX and nitrogen and in selected measures of lower extremity performance will be compared across the three groups. The safety and tolerability of the interventions will also be evaluated. This investigation should provide needed information on the appropriate dosing regimen for men and women and on the study population that should be enrolled in a future bicarbonate intervention trial to assess the long-term effects of this simple, low cost intervention on important clinical outcomes including rates of loss in bone and muscle mass, falls, and fractures.
Detailed description
This dose-finding study will evaluate the effects of placebo and two doses of bicarbonate on urinary NTX and nitrogen excretion and on lower extremity performance over a three month period. The lower dose is similar to the dose shown in our recent trial to be effective. This study is a double blind, randomized, placebo-controlled, parallel-group trial in which 138 healthy men and 138 women, age 60 and older, will take potassium bicarbonate in doses of 1.0 or 1.5 mmol/kg of body weight or placebo daily for three months. Changes in urinary excretion of NTX and nitrogen and in measures of lower extremity performance will be compared across the three groups. The safety and tolerability of the interventions will also be evaluated. This investigation should provide needed information on the appropriate dosing regimen and on the study population that should be enrolled in a future bicarbonate intervention trial to assess the long-term effects of this simple, low cost intervention on important clinical outcomes including rates of loss in bone and muscle mass, falls, and fractures.
Interventions
potassium bicarbonate in dose of 1.0 mmol/kg per day, given in three even daily doses after meals with a full glass of water
microcrystalline cellulose
Sponsors
Study design
Eligibility
Inclusion criteria
* men and women * age 60 and older * community dwelling * women 1 yr since last menses
Exclusion criteria
Medications: 1. Oral glucocorticoids for \> 10 days in the last 3 months * Cortef (hydrocortisone) * Prednisone 2. Parenteral glucocorticoids • Decadron (dexamethasone) 3. Osteoporosis medications in the last 6 months * Forteo (teriparatide) * Calcimar, Miacalcin (calcitonin) * Evista (raloxifene) 4. Osteoporosis medications in the last 2 years * Fosamax (alendronate) * Didronel (etidronate) * Aredia (pamidronate) * Actonel (risedronate) * Reclast (zoledronate) 5. Tamoxifen in the last 6 months 6. Calcium/Parathyroid * Rocaltrol (calcitriol) * Zemplar (paricalcitol) * Drisdol, Ergocalciferol 7. Diuretics currently * hydrocholorothiazide (HCTZ) * Diuril (chlorothiazide) * Thalitone (chlorthalidone) * Zaroxolyn (metolazone) * Dyazide * Maxide * Moduretic * Lasix (forosamine) * Dyrenium (triamterene) * Midamor 8. Testosterone or estrogen in the last 6 months (vaginal estrogen okay) 9. Angiotensin converting enzyme (ACE) inhibitors currently * Benazepril (Lotensin) * Captopril (Capoten) * Enalapril (Vasotec) * Fosinopril (Monopril) * Lisinopril (Prinivil, Zestril) * Moexipril (Univasc) * Perindopril (Aceon) * Quinapril (Accupril) * Ramipril (Altace) * Trandolapril (Mavik) 10. Angiotensin II receptor blockers currently * Candesartan (Atacand) * Eprosartan (Teveten) * Irbesartan (Avapro) * Losartan (Cozaar) * Olmesartan (Benicar) * Telmisartan (Micardis) * Valsartan (Diovan) Over-the-Counter Drugs currently 1. Antacids - any antacid that contains calcium carbonate, aluminum hydroxide, magnesium hydroxide, or calcium acetate - selected examples include * TUMS * Mylanta * Maalox * Titralac * Rolaids * Sodium bicarbonate (baking soda) * Note: magaldrate or Riopan® is allowed 2. Potassium supplements 3. Salt substitutes Conditions/Diseases 1. renal disease including kidney stones in the past 5 years or glomerular filtration rate (GFR) \< 60 ml/min/1.73 m2 2. hyperkalemia (serum potassium \>5.3 meq/L; normal range 3.5-5.3 meq/L) 3. elevated serum bicarbonate (serum bicarbonate \> 29 mmol/L; normal range 22-29 mmol/L) 4. cirrhosis 5. gastroesophageal reflux disease (GERD) requiring treatment with alkali-containing antacids (TUMS, Mylanta, Maalox, Titralac, Rolaids, or sodium bicarbonate) 6. hyperparathyroidism 7. untreated thyroid disease 8. significant immune disorder such as rheumatoid arthritis 9. current unstable heart disease 10. active malignancy or cancer therapy in the last year 11. fasting spot urine calcium/creatinine \> 0.38 mmol/mmol after 1 wk off of calcium supplements 12. congestive heart failure, arrhythmias (surgically treated arrhythmias acceptable), or myocardial infarction in last 12 months 13. serum calcium outside the normal range of 8.3-10.2 mg/dl 14. uncontrolled diabetes mellitus (fasting blood sugar \> 130) 15. alcohol use exceeding 2 drinks/day 16. peptic ulcers or esophageal stricture 17. weight \<45 or \>113.5 kg (\<99 or \>249.7 lbs) 18. other abnormalities in screening labs, at discretion of the study physician (the PI)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Dose of Potassium Bicarbonate Needed for Maximal Suppression of 24-hr Urinary N-telopeptide | 84 days | Describe and compare changes in urinary N-telopeptide (NTX) across the placebo and Potassium Bicarbonate (KHCO3) doses. |
| Co-primary Aim - to Identify the Dose of KHCO3 Needed for Maximal Suppression of 24-hr Urinary Nitrogen | 84 days | Describe and compare changes in 24-hour urinary nitrogen in the low and high dose and KHCO3 group and in placebo. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Potassium Bicarbonate Low Dose potassium bicarbonate in dose of 1.0 mmol/kg per day, given in three even daily doses after meals with a full glass of water
potassium bicarbonate: potassium bicarbonate in dose of 1.0 mmol/kg per day, given in three even daily doses after meals with a full glass of water | 84 |
| Potassium Bicarbonate Higher Dose potassium bicarbonate in dose of 1.5 mmol/kg per day, given in three even daily doses after meals with a full glass of water
potassium bicarbonate: potassium bicarbonate in dose of 1.5 mmol/kg per day, given in three even daily doses after meals with a full glass of water | 79 |
| Inactive Placebo Capsule microcrystalline cellulose
placebo: microcrystalline cellulose | 81 |
| Total | 244 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 | 1 |
| Overall Study | Physician Decision | 2 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 4 | 1 |
Baseline characteristics
| Characteristic | Total | Inactive Placebo Capsule | Potassium Bicarbonate Higher Dose | Potassium Bicarbonate Low Dose |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 123 Participants | 40 Participants | 39 Participants | 44 Participants |
| Age, Categorical Between 18 and 65 years | 121 Participants | 41 Participants | 40 Participants | 40 Participants |
| Age, Continuous | 66.9 years STANDARD_DEVIATION 5.6 | 66.8 years STANDARD_DEVIATION 6.1 | 66.4 years STANDARD_DEVIATION 5.1 | 67.4 years STANDARD_DEVIATION 5.5 |
| Glomerular Filtration Rate (GFR) | 76.3 ml/min/1.73m^2 STANDARD_DEVIATION 13 | 74.8 ml/min/1.73m^2 STANDARD_DEVIATION 12.9 | 77.5 ml/min/1.73m^2 STANDARD_DEVIATION 12.8 | 76.5 ml/min/1.73m^2 STANDARD_DEVIATION 13.2 |
| Race/Ethnicity, Customized African-American | 18 participants | 3 participants | 9 participants | 6 participants |
| Race/Ethnicity, Customized Asian | 2 participants | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Caucasian, Hispanic | 5 participants | 2 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Caucasian, Non-hispanic | 219 participants | 75 participants | 68 participants | 76 participants |
| Region of Enrollment United States | 244 participants | 81 participants | 79 participants | 84 participants |
| Serum bicarbonate | 26.0 mmol/L STANDARD_DEVIATION 2.2 | 26.1 mmol/L STANDARD_DEVIATION 2.4 | 25.8 mmol/L STANDARD_DEVIATION 2.4 | 26.1 mmol/L STANDARD_DEVIATION 1.9 |
| Serum potassium | 4.33 meq/L STANDARD_DEVIATION 0.32 | 4.30 meq/L STANDARD_DEVIATION 0.31 | 4.39 meq/L STANDARD_DEVIATION 0.36 | 4.31 meq/L STANDARD_DEVIATION 0.29 |
| Sex: Female, Male Female | 118 Participants | 38 Participants | 39 Participants | 41 Participants |
| Sex: Female, Male Male | 126 Participants | 43 Participants | 40 Participants | 43 Participants |
| Urine calcium/creatinine | 104 mg/g STANDARD_DEVIATION 55 | 114 mg/g STANDARD_DEVIATION 69 | 99 mg/g STANDARD_DEVIATION 48 | 99 mg/g STANDARD_DEVIATION 43 |
| Weight | 74.1 kg STANDARD_DEVIATION 13.6 | 73.2 kg STANDARD_DEVIATION 14 | 74.2 kg STANDARD_DEVIATION 13 | 74.8 kg STANDARD_DEVIATION 13.7 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 19 / 84 | 29 / 79 | 23 / 81 |
| serious Total, serious adverse events | 3 / 84 | 3 / 79 | 1 / 81 |
Outcome results
Co-primary Aim - to Identify the Dose of KHCO3 Needed for Maximal Suppression of 24-hr Urinary Nitrogen
Describe and compare changes in 24-hour urinary nitrogen in the low and high dose and KHCO3 group and in placebo.
Time frame: 84 days
Population: healthy men and women age 60 years and older
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Potassium Bicarbonate Low Dose | Co-primary Aim - to Identify the Dose of KHCO3 Needed for Maximal Suppression of 24-hr Urinary Nitrogen | baseline 24-hr urine nitrogen | 769 mmol/day | Standard Error 32 |
| Potassium Bicarbonate Low Dose | Co-primary Aim - to Identify the Dose of KHCO3 Needed for Maximal Suppression of 24-hr Urinary Nitrogen | change in 24-hr urine nitrogen | -29.4 mmol/day | Standard Error 18.6 |
| Potassium Bicarbonate Higher Dose | Co-primary Aim - to Identify the Dose of KHCO3 Needed for Maximal Suppression of 24-hr Urinary Nitrogen | baseline 24-hr urine nitrogen | 834 mmol/day | Standard Error 39 |
| Potassium Bicarbonate Higher Dose | Co-primary Aim - to Identify the Dose of KHCO3 Needed for Maximal Suppression of 24-hr Urinary Nitrogen | change in 24-hr urine nitrogen | -16.4 mmol/day | Standard Error 19.1 |
| Inactive Placebo Capsule | Co-primary Aim - to Identify the Dose of KHCO3 Needed for Maximal Suppression of 24-hr Urinary Nitrogen | baseline 24-hr urine nitrogen | 864 mmol/day | Standard Error 33 |
| Inactive Placebo Capsule | Co-primary Aim - to Identify the Dose of KHCO3 Needed for Maximal Suppression of 24-hr Urinary Nitrogen | change in 24-hr urine nitrogen | -21.0 mmol/day | Standard Error 18.7 |
The Dose of Potassium Bicarbonate Needed for Maximal Suppression of 24-hr Urinary N-telopeptide
Describe and compare changes in urinary N-telopeptide (NTX) across the placebo and Potassium Bicarbonate (KHCO3) doses.
Time frame: 84 days
Population: Healthy men and women age 60 years and older
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Potassium Bicarbonate Low Dose | The Dose of Potassium Bicarbonate Needed for Maximal Suppression of 24-hr Urinary N-telopeptide | baseline 24-hr urinary NTX | 240 nmol/day | Standard Error 17 |
| Potassium Bicarbonate Low Dose | The Dose of Potassium Bicarbonate Needed for Maximal Suppression of 24-hr Urinary N-telopeptide | change in NTX | -53 nmol/day | Standard Error 11 |
| Potassium Bicarbonate Higher Dose | The Dose of Potassium Bicarbonate Needed for Maximal Suppression of 24-hr Urinary N-telopeptide | baseline 24-hr urinary NTX | 230 nmol/day | Standard Error 20 |
| Potassium Bicarbonate Higher Dose | The Dose of Potassium Bicarbonate Needed for Maximal Suppression of 24-hr Urinary N-telopeptide | change in NTX | -43 nmol/day | Standard Error 11 |
| Inactive Placebo Capsule | The Dose of Potassium Bicarbonate Needed for Maximal Suppression of 24-hr Urinary N-telopeptide | baseline 24-hr urinary NTX | 241 nmol/day | Standard Error 17 |
| Inactive Placebo Capsule | The Dose of Potassium Bicarbonate Needed for Maximal Suppression of 24-hr Urinary N-telopeptide | change in NTX | -14 nmol/day | Standard Error 11 |