Musculoskeletal Effects of Bicarbonate

• Sponsor: Tufts University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01475214
• Collaborator: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (NIH)
• Enrollment: 244
• Location: 1
• Arms: 3
• Duration (Months): 43
• Patients Per Site Per Month: 5.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Muscle Loss; Fractures; Osteoporosis, Age Related; Fall Injury	Dietary Supplement: potassium bicarbonate; Dietary Supplement: potassium bicarbonate; Other: Inactive placebo capsule	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 244 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: Musculoskeletal Benefits of Bicarbonate in Older Adults - A Dose-Finding Trial
• Study Start Date: Jan 1, 2012
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Aug 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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	Dietary Supplement: 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
Active Comparator: 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	Dietary Supplement: 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
Placebo Comparator: placebo microcrystalline cellulose	Other: Inactive placebo capsule; microcrystalline cellulose

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

1. Parenteral glucocorticoids

• Decadron (dexamethasone)

1. Osteoporosis medications in the last 6 months

• Forteo (teriparatide)

• Calcimar, Miacalcin (calcitonin)

• Evista (raloxifene)

1. Osteoporosis medications in the last 2 years

• Fosamax (alendronate)

• Didronel (etidronate)

• Aredia (pamidronate)

• Actonel (risedronate)

• Reclast (zoledronate)

1. Tamoxifen in the last 6 months

2. Calcium/Parathyroid

• Rocaltrol (calcitriol)

• Zemplar (paricalcitol)

• Drisdol, Ergocalciferol

1. Diuretics currently

• hydrocholorothiazide (HCTZ)

• Diuril (chlorothiazide)

• Thalitone (chlorthalidone)

• Zaroxolyn (metolazone)

• Dyazide

• Maxide

• Moduretic

• Lasix (forosamine)

• Dyrenium (triamterene)

• Midamor

1. Testosterone or estrogen in the last 6 months (vaginal estrogen okay)

2. 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)

1. 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

1. Potassium supplements

2. 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University	Boston	Massachusetts	United States	02111

Sponsors and Collaborators

• Tufts University
• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Investigators

• Principal Investigator: Bess Dawson-Hughes, M.D., Tufts University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Bess Dawson-Hughes, Professor of Medicine, Tufts University
• ClinicalTrials.gov Identifier: NCT01475214
• Other Study ID Numbers: 2705; R01AR060261
• First Posted: Nov 21, 2011
• Last Update Posted: Oct 19, 2015
• Last Verified: Sep 1, 2015

• Keywords provided by Bess Dawson-Hughes, Professor of Medicine, Tufts University: potassium bicarbonate; urinary N-telopeptide; urinary nitrogen; net acid excretion
• Additional relevant MeSH terms: Osteoporosis

Study Results

Participant Flow

Arm/Group Title	Potassium Bicarbonate Low Dose	Potassium Bicarbonate Higher Dose	Inactive Capsule
Arm/Group Description	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	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	microcrystalline cellulose placebo: microcrystalline cellulose
Period Title: Overall Study
STARTED	84	79	81
COMPLETED	79	75	79
NOT COMPLETED	5	4	2

Baseline Characteristics

Arm/Group Title	Potassium Bicarbonate Low Dose	Potassium Bicarbonate Higher Dose	Inactive Placebo Capsule	Total
Arm/Group Description	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	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	microcrystalline cellulose placebo: microcrystalline cellulose	Total of all reporting groups
Overall Participants	84	79	81	244
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	40 47.6%	40 50.6%	41 50.6%	121 49.6%
>=65 years	44 52.4%	39 49.4%	40 49.4%	123 50.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.4 (5.5)	66.4 (5.1)	66.8 (6.1)	66.9 (5.6)
Sex: Female, Male (Count of Participants)
Female	41 48.8%	39 49.4%	38 46.9%	118 48.4%
Male	43 51.2%	40 50.6%	43 53.1%	126 51.6%
Race/Ethnicity, Customized (participants) [Number]
Caucasian, Non-hispanic	76 90.5%	68 86.1%	75 92.6%	219 89.8%
Caucasian, Hispanic	2 2.4%	1 1.3%	2 2.5%	5 2%
African-American	6 7.1%	9 11.4%	3 3.7%	18 7.4%
Asian	0 0%	1 1.3%	1 1.2%	2 0.8%
Region of Enrollment (participants) [Number]
United States	84 100%	79 100%	81 100%	244 100%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	74.8 (13.7)	74.2 (13.0)	73.2 (14.0)	74.1 (13.6)
Glomerular Filtration Rate (GFR) (ml/min/1.73m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ml/min/1.73m^2]	76.5 (13.2)	77.5 (12.8)	74.8 (12.9)	76.3 (13.0)
Serum potassium (meq/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meq/L]	4.31 (0.29)	4.39 (0.36)	4.30 (0.31)	4.33 (0.32)
Serum bicarbonate (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	26.1 (1.9)	25.8 (2.4)	26.1 (2.4)	26.0 (2.2)
Urine calcium/creatinine (mg/g) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/g]	99 (43)	99 (48)	114 (69)	104 (55)

Outcome Measures

1. Primary Outcome

Title	The Dose of Potassium Bicarbonate Needed for Maximal Suppression of 24-hr Urinary N-telopeptide
Description	Describe and compare changes in urinary N-telopeptide (NTX) across the placebo and Potassium Bicarbonate (KHCO3) doses.
Time Frame	84 days

Outcome Measure Data

Analysis Population Description

Healthy men and women age 60 years and older

Arm/Group Title	Potassium Bicarbonate Low Dose	Potassium Bicarbonate Higher Dose	Inactive Placebo Capsule
Arm/Group Description	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	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	microcrystalline cellulose placebo: microcrystalline cellulose
Measure Participants	79	75	79
baseline 24-hr urinary NTX	240 (17)	230 (20)	241 (17)
change in NTX	-53 (11)	-43 (11)	-14 (11)

2. Primary Outcome

Title	Co-primary Aim - to Identify the Dose of KHCO3 Needed for Maximal Suppression of 24-hr Urinary Nitrogen
Description	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

Outcome Measure Data

Analysis Population Description

healthy men and women age 60 years and older

Arm/Group Title	Potassium Bicarbonate Low Dose	Potassium Bicarbonate Higher Dose	Inactive Capsule
Arm/Group Description	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	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	microcrystalline cellulose placebo: microcrystalline cellulose
Measure Participants	79	75	79
baseline 24-hr urine nitrogen	769 (32)	834 (39)	864 (33)
change in 24-hr urine nitrogen	-29.4 (18.6)	-16.4 (19.1)	-21.0 (18.7)

Adverse Events

Time Frame	84 days
Arm/Group Title	Potassium Bicarbonate Low Dose		Potassium Bicarbonate Higher Dose		Inactive Capsule
Arm/Group Description	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		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		microcrystalline cellulose placebo: microcrystalline cellulose
All Cause Mortality
	Potassium Bicarbonate Low Dose		Potassium Bicarbonate Higher Dose		Inactive Capsule
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Potassium Bicarbonate Low Dose		Potassium Bicarbonate Higher Dose		Inactive Capsule
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/84 (3.6%)		3/79 (3.8%)		1/81 (1.2%)
Cardiac disorders
Abdominal aortic repair	0/84 (0%)	0	0/79 (0%)	0	1/81 (1.2%)	1
Gastrointestinal disorders
GI upset	1/84 (1.2%)	1	0/79 (0%)	0	0/81 (0%)	0
Musculoskeletal and connective tissue disorders
Contusions/abrasions	1/84 (1.2%)	1	1/79 (1.3%)	1	0/81 (0%)	0
Fracture	0/84 (0%)	0	1/79 (1.3%)	1	0/81 (0%)	0
Renal and urinary disorders
High serum potassium	0/84 (0%)	0	1/79 (1.3%)	1	0/81 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonia	1/84 (1.2%)	1	0/79 (0%)	0	0/81 (0%)	0
Other (Not Including Serious) Adverse Events
	Potassium Bicarbonate Low Dose		Potassium Bicarbonate Higher Dose		Inactive Capsule
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/84 (22.6%)		29/79 (36.7%)		23/81 (28.4%)
Cardiac disorders
Heart palpitations	0/84 (0%)	0	1/79 (1.3%)	1	1/81 (1.2%)	1
Eye disorders
Cataract	1/84 (1.2%)	1	0/79 (0%)	0	0/81 (0%)	0
Gastrointestinal disorders
GI upset	5/84 (6%)	5	9/79 (11.4%)	11	6/81 (7.4%)	6
Constipation/diarrhea	1/84 (1.2%)	1	1/79 (1.3%)	1	1/81 (1.2%)	1
General disorders
Headache	1/84 (1.2%)	1	1/79 (1.3%)	1	2/81 (2.5%)	2
Fever, fatigue	0/84 (0%)	0	0/79 (0%)	0	1/81 (1.2%)	1
dizziness	1/84 (1.2%)	1	2/79 (2.5%)	2	0/81 (0%)	0
Mouth irritation	0/84 (0%)	0	0/79 (0%)	0	1/81 (1.2%)	1
Musculoskeletal and connective tissue disorders
Knee/hip injury	1/84 (1.2%)	1	2/79 (2.5%)	2	0/81 (0%)	0
Sprain	0/84 (0%)	0	0/79 (0%)	0	3/81 (3.7%)	3
Numbness	0/84 (0%)	0	1/79 (1.3%)	1	0/81 (0%)	0
Renal and urinary disorders
High serum potassium	5/84 (6%)	7	8/79 (10.1%)	10	5/81 (6.2%)	9
low GFR	4/84 (4.8%)	5	3/79 (3.8%)	3	3/81 (3.7%)	3
Respiratory, thoracic and mediastinal disorders
Upper respiratory infection	0/84 (0%)	0	0/79 (0%)	0	1/81 (1.2%)	1
Skin and subcutaneous tissue disorders
Skin cyst	0/84 (0%)	0	1/79 (1.3%)	1	0/81 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.