Musculoskeletal Effects of Bicarbonate

Study Overview
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Brief Summary
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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
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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.

Official Title
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Musculoskeletal Benefits of Bicarbonate in Older Adults - A Dose-Finding Trial

Conditions
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Muscle Loss, Fractures, Osteoporosis, Age Related, Fall Injury

Intervention / Treatment
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* Dietary Supplement: potassium bicarbonate
* Dietary Supplement: potassium bicarbonate
* Other: Inactive placebo capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: men and women age 60 and older community dwelling women 1 yr since last menses Exclusion Criteria: Medications: Oral glucocorticoids for > 10 days in the last 3 months Cortef (hydrocortisone) Prednisone Parenteral glucocorticoids • Decadron (dexamethasone) Osteoporosis medications in the last 6 months Forteo (teriparatide) Calcimar, Miacalcin (calcitonin) Evista (raloxifene) Osteoporosis medications in the last 2 years Fosamax (alendronate) Didronel (etidronate) Aredia (pamidronate) Actonel (risedronate) Reclast (zoledronate) Tamoxifen in the last 6 months Calcium/Parathyroid Rocaltrol (calcitriol) Zemplar (paricalcitol) Drisdol, Ergocalciferol Diuretics currently hydrocholorothiazide (HCTZ) Diuril (chlorothiazide) Thalitone (chlorthalidone) Zaroxolyn (metolazone) Dyazide Maxide Moduretic Lasix (forosamine) Dyrenium (triamterene) Midamor Testosterone or estrogen in the last 6 months (vaginal estrogen okay) 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) Angiotensin II receptor blockers currently Candesartan (Atacand) Eprosartan (Teveten) Irbesartan (Avapro) Losartan (Cozaar) Olmesartan (Benicar) Telmisartan (Micardis) Valsartan (Diovan) Over-the-Counter Drugs currently 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 Potassium supplements Salt substitutes Conditions/Diseases renal disease including kidney stones in the past 5 years or glomerular filtration rate (GFR) < 60 ml/min/1.73 m2 hyperkalemia (serum potassium >5.3 meq/L; normal range 3.5-5.3 meq/L) elevated serum bicarbonate (serum bicarbonate > 29 mmol/L; normal range 22-29 mmol/L) cirrhosis gastroesophageal reflux disease (GERD) requiring treatment with alkali-containing antacids (TUMS, Mylanta, Maalox, Titralac, Rolaids, or sodium bicarbonate) hyperparathyroidism untreated thyroid disease significant immune disorder such as rheumatoid arthritis current unstable heart disease active malignancy or cancer therapy in the last year fasting spot urine calcium/creatinine > 0.38 mmol/mmol after 1 wk off of calcium supplements congestive heart failure, arrhythmias (surgically treated arrhythmias acceptable), or myocardial infarction in last 12 months serum calcium outside the normal range of 8.3-10.2 mg/dl uncontrolled diabetes mellitus (fasting blood sugar > 130) alcohol use exceeding 2 drinks/day peptic ulcers or esophageal stricture weight <45 or >113.5 kg (<99 or >249.7 lbs) other abnormalities in screening labs, at discretion of the study physician (the PI)

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: potassium bicarbonate low dose<br>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 | Dietary Supplement: potassium bicarbonate<br>* 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<br>|
| Active Comparator: potassium bicarbonate higher dose<br>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 | Dietary Supplement: potassium bicarbonate<br>* 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<br>|
| Placebo Comparator: placebo<br>microcrystalline cellulose | Other: Inactive placebo capsule<br>* microcrystalline cellulose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 84 days | 
| 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. | 84 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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potassium bicarbonate, urinary N-telopeptide, urinary nitrogen, net acid excretion