Participants were recruited from a single academic center. Subjects underwent screening at the Clinical Translational Science Center (CTSC) at Weill Cornell Medical College (WCMC). Study visits occurred at the CTSC where investigators administered and monitored questionnaires, compliance, adverse events, and endpoint measurements. Subjects were assigned an anonymous study number at the beginning of the trial, which was used to track the participant's data throughout the study. The protocol was approved by the Institutional Review Board (IRB) and the procedures followed were in accordance with the ethical standards of the IRB and the CTSC. All patients provided informed consent.
Treatment Groups Participants were assigned to either the treatment or placebo group using a randomization schema generated by the statistician. The randomization method was blocked randomization with a blocking factor of 4. The blocked randomization was not stratified by any other factors. The study was conducted in a double blind manner. The study medication, K-citrate, or placebo, was dispensed through the New York Presbyterian Hospital (NYPH) pharmacy. Bottles in the pharmacy were sequentially numbered and the number was linked to the blocked randomization scheme. Only the statistician and the pharmacist knew the meaning of the numbered codes and only the statistician knew the blocking assignment. Blocked randomization with balanced randomization of each block and blocks of the same size was performed by the RANDOM procedure within the WinPepi Version 11.1.
Investigators who administered questionnaires and assessed compliance, adverse effects or endpoint information were blind to group assignment. Only study investigators were able to enroll participants in the study and assign them to treatment arms. Those assigned to the treatment group received the study drug (40 mEq daily K Citrate: two 10 mEq tablets twice daily); those assigned to the control group received inert tablets of the same quantity. All participants received daily supplementation with Citracal (630 mg calcium citrate and 400 IU vitamin D3 per two caplets). All supplements and medications were provided by Mission Pharmacal/Bayer Pharmaceuticals in Boerne, Texas. Subjects discontinued their prior supplements at the time of entry to the study and were advised to adhere to the standardized supplementation regimen outlined by the protocol.
Measurements and Outcomes Subjects were evaluated at baseline, 1, 3, 6, and 12 months. The following outcomes were measured: change in bone turnover markers including u-NTX, BSAP, OC and P1NP; changes in 24 hour urinary concentrations of citrate, sulfate, and calcium; and changes in BMD measured from baseline to 12 months. Adverse events and compliance were measured at each visit over the study duration. Adverse events pertained to medication side effects, including, but not limited to, gastrointestinal complaints, nausea, diarrhea, and stomach pain, as well as the development of hyperkalemia or metabolic acidosis. If any of the following occurred, potassium exceeded 5.2 mmol/L; bicarbonate level exceeded 32 mmol/L; creatinine increased by more than 30% or rose above 2.0 ng/dL; or GFR was \< 60, study medications were stopped until the parameter normalized, at which point the medication was resumed at half dose: Compliance was assessed by remaining pill count; good compliance was defined at ≤ 20% of pills remaining, or ≤ 18 pills remaining for each 3-month dose allocation.
Baseline measurements included dietary assessment (block food frequency questionnaire) and blood pressure. Laboratory evaluation was performed at the General Core Laboratory at WCMC and included a basic metabolic panel, calcium, albumin and thyroid stimulating hormone (TSH). 25-OH and 1,25(OH)2 Vitamin D were measured by radioimmunoassay (Immunodiagnostic Systems, Scottsdale, Arizona). The interassay coefficient of variation (CV) was \<8.2% and \<13%, respectively. Intact parathyroid hormone (i-PTH) was measured by immunoradiometric assay (Scantibodies Laboratories, Santee, California; CV \<6.4%). Markers of bone turnover included osteocalcin (OC: quantitative immunoradiometric assay, DiaSorin, Stillwater, Minnesota; CV \<9.5%) , bone specific alkaline phosphatase (BSAP: solid phase monoclonal antibody immunoenzymetric assay, Immunodiagnostics Systems, Scottsdale, Arizona; CV\<6.4%), procollagen type 1 amino-terminal propeptide (P1NP: quantitative radioimmunoassay, Orion Diagnostica, Espoo, Finland; CV\<9.8%), urinary N-telopeptide (U-NTX: quantitative enzyme-linked immunosorbent assay kit, Wampole Laboratories INC Princeton, New Jersey; CV\<5.0%). All specimens were collected as fasting morning samples. The urinary-NTX was a second morning void. The specimens were frozen and batch analyzed. 24 hour urinary collections for calcium, creatinine, sulfate, citrate and sodium were analyzed at Quest Diagnostics. BMD was performed at lumbar spine, total hip and femoral neck using dual-energy X-ray Absorptiometry (DXA) Hologic; Bedford, Massachusetts. The least significant change (LSC) for the DXA was 0.025 at the lumbar spine, 0.025 at the femoral neck and 0.015 at the radius. Two technologists, both certified by the International Society for Clinical Densitometry, performed all DXA testing on the participants.
