Vitamin D Repletion in Primary Hyperparathyroidism

• Bone-specific alkaline phosphatase [ Time Frame: 1 year ] [ Designated as safety issue: No ]
• Areal bone mineral density of the lumbar spine [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  measured by DXA
• Trabecular bone density at the forearm [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  Measured by high resolution peripheral quantitative computed tomography
• Volumetric bone density of the spine [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  Assessed by central quantitative computed tomography
• Elastic Stiffness at the radius as assessed by finite element analysis of HRpQCT images [ Time Frame: 1 year ] [ Designated as safety issue: No ]
• Serum Calcium Concentration [ Time Frame: Week 8, Week 12 ] [ Designated as safety issue: Yes ]
  Participants whose serum calcium concentration rise above 12 milligrams per deciliter (mg/dL) will stop study medications
• Urinary Calcium Level [ Time Frame: Week 8, Week 12 ] [ Designated as safety issue: Yes ]
  Urinary calcium > 400 milligrams/day (mg/d)
• nephrolithiasis [ Time Frame: 1, 3, 6 9 and 12 months ] [ Designated as safety issue: Yes ]
  Participants who develop nephrolithiasis will stop study medications
• Serum C-terminal telopeptide of type I collagen [ Time Frame: 1 year ] [ Designated as safety issue: No ]
• Areal bone mineral density of the hip [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  Measured by DXA
• Trabecular bone density at the tibia [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  measured by high resolution peripheral quantitative computed tomography
• Cortical bone density of the radius [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  Measured by high resolution peripheral quantitative computed tomography
• Cortical bone density at the tibia [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  measured by high resolution quantitative computed tomography
• Volumetric bone density of the hip [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  measured by central quantitative computed tomography
• Elastic Stiffness at the tibia as assessed by finite element analysis of HRpQCT images [ Time Frame: 1 year ] [ Designated as safety issue: No ]
• Number of participants achieving a serum vitamin D level greater than or equal to 30 nanograms per milliliter [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Primary hyperparathyroidism (PHPT) is a common disease in which the parathyroid glands produce excessive amounts of parathyroid hormone (PTH), which regulates calcium levels. In primary hyperparathyroidism, high levels of PTH remove too much calcium from bones and deposit the excess calcium in the blood, which is then filtered into the urine by the kidneys. Bone health is threatened by the excess calcium loss which weakens the structure of the bones.

Many patients with primary hyperparathyroidism also have low vitamin D (25OHD) levels which is thought to further impair bone health. Recent medical guidelines recommend treating patients with primary hyperparathyroidism who have low vitamin D levels with oral vitamin D but the optimal vitamin D dose and rate of repletion is unclear.

It is, therefore, important to determine if replenishing Vitamin D will improve bone health in primary hyperparathyroidism, and if so, to assess the impact of the rate of vitamin D is repletion. This study will compare three vitamin D regimens to determine if vitamin D supplementation improves the biochemical features of primary hyperparathyroidism as well as bone density, bone microarchitecture and bone strength. Additionally, we will determine which regimen results in the greatest improvement.

Study Design

99 patients with PHPT and vitamin D deficiency (25OHD less than 30 nanograms/milliliter (ng/ml)) will be enrolled and randomized 1:1:1 to 3 different vitamin D repletion regimens: 1) 50,000 international units (IU) vitamin D3/week for 4 weeks plus a daily multivitamin with 400 IU vitamin D, followed by 50,000 IU vitamin D/month plus a daily multivitamin for 11 months 2) 12,000 IU vitamin D3/wk plus a daily multivitamin with 400 IU vitamin D for 12 months 3)placebo plus a daily multivitamin with 400 IU vitamin D for 12 months.

Study Procedures

1. Blood tests
2. Urine calcium excretion
3. Bone Mineral Densitometry assessed with dual x-ray absorptiometry (DXA)
4. High Resolution Peripheral Quantitative Computed Tomography (HR-pQCT), which provides measures of volumetric density and bone size, and microarchitecture at the forearm and tibia
5. Central Quantitative Computed Tomography (cQCT) of the spine and hip

• Primary Hyperparathyroidism
• Vitamin D Deficiency

• Dietary Supplement: 50,000 IU Vitamin D3

  Month 1: 50,000 IU vitamin D3 once a week, plus daily multivitamin with 400 IU vitamin D.

  Months 2-12: 50,000 IU vitamin D3 once a month, 3 weeks placebo, plus daily multivitamin with 400 IU vitamin D.

• Dietary Supplement: 12,000 IU Vitamin D3

  Month 1: 12,000 IU vitamin D3 once a week, plus daily multivitamin with 400 IU vitamin D.

  Months 2-12: 12,000 IU vitamin D3 a week, plus daily multivitamin with 400 IU vitamin D.

• Dietary Supplement: Placebo

  Month1: Placebo every week plus daily multivitamin with 400 IU vitamin D.

  Months 2-12 placebo every week plus daily multivitamin with 400 IU vitamin D.

• Experimental: Group 1
  50,000 IU Vitamin D3 plus a multivitamin with 400 IU vitamin D
  Intervention: Dietary Supplement: 50,000 IU Vitamin D3
• Experimental: Group 2
  12,000 IU Vitamin D3 plus a multivitamin with 400 IU vitamin D
  Intervention: Dietary Supplement: 12,000 IU Vitamin D3
• Placebo Comparator: Group 3
  Placebo plus a multivitamin with 400 IU vitamin D
  Intervention: Dietary Supplement: Placebo

Inclusion Criteria:

• Diagnosed PHPT, defined by an elevated serum calcium level (we will not study normocalcemic PHPT) with elevated or inappropriately normal PTH levels.
• Vitamin D3 less than 30 ng/ml

Exclusion Criteria:

• Premenopausal women
• African Americans (altered vitamin D metabolism)
• Patients with a BMI greater than 35 (altered vitamin D metabolism);
• Patients with familial hyperparathyroid syndromes
• Current or past use of the following medications: bisphosphonate within past 2 years, use of lithium or thiazide diuretics, current use of cinacalcet, use of aluminum containing medications, cimetidine, colestipol, or orlistat
• Malignancy, except cured basal or squamous cell skin carcinoma or other cured cancers that are at least five years free from recurrence
• History or current diagnosis of certain medical diseases (including sarcoidosis, active infectious granulomatous disease, HIV/AIDS, chronic kidney disease (estimated glomerular filtration rate less than 60 ml/min), liver disease; GI diseases known to affect calcium metabolism; secondary hyperparathyroidism);
• We will also exclude patients with calcium above 11.5 mg/dL, urine calcium above 350 mg/day, and active nephrolithiasis because vitamin D repletion could potentially exacerbate hypercalcemia or hypercalciuria
• Other exclusions include protected individuals (institutionalized), prisoners, and any other prospective participant who might not be able to give voluntary informed consent.