What could be the cause of a patient's bone pain, fatigue, severe muscle weakness, muscle twitching, and dry skin, with lab results showing hypocalcemia, mildly impaired renal function, and vitamin D deficiency?

Likely Diagnosis: Secondary Hyperparathyroidism Due to Vitamin D Insufficiency with Metabolic Acidosis

This patient's presentation is most consistent with secondary hyperparathyroidism driven by vitamin D insufficiency (level 33 ng/mL, which is borderline), combined with metabolic acidosis (bicarbonate 17 mmol/L) and borderline hypocalcemia (calcium 9.4 mg/dL). The constellation of bone pain, severe muscle weakness, muscle twitching, and fatigue are classic manifestations of this condition.

Primary Pathophysiologic Process

The core issue is vitamin D insufficiency leading to impaired calcium absorption and secondary hyperparathyroidism, compounded by metabolic acidosis which further depletes bone mineral stores. 1

• Vitamin D level of 33 ng/mL is at the lower threshold of adequacy—levels below 30 ng/mL definitively indicate insufficiency, and levels between 30-40 ng/mL may still be associated with elevated PTH and impaired calcium homeostasis 2
• The calcium of 9.4 mg/dL is in the low-normal range (normal 8.4-10.2 mg/dL), which in the context of vitamin D insufficiency suggests inadequate intestinal calcium absorption 2
• Metabolic acidosis (bicarbonate 17 mmol/L, normal >22 mmol/L) independently contributes to bone demineralization and muscle weakness 2

Clinical Manifestations Explained

Each symptom directly correlates with the underlying mineral and acid-base disturbances:

• Bone pain: Results from osteomalacia (defective bone mineralization) due to vitamin D insufficiency and secondary hyperparathyroidism 3
• Severe muscle weakness and fatigue: Vitamin D deficiency causes myopathy through impaired muscle calcium handling; metabolic acidosis exacerbates muscle dysfunction 3
• Muscle twitching: Reflects neuromuscular irritability from borderline hypocalcemia and possible ionized calcium reduction 4
• Dry skin: Can be associated with chronic metabolic disturbances and vitamin D deficiency

Additional Laboratory Considerations

The elevated anion gap (17.3 mEq/L, normal 8-12) with low bicarbonate indicates a high anion gap metabolic acidosis, which requires investigation for underlying causes 2:

• The mildly elevated creatinine (1.29 mg/dL) suggests possible early chronic kidney disease (CKD stage 3a if GFR 45-59 mL/min/1.73m²), which could contribute to both acidosis and impaired vitamin D activation 2
• Homocysteine of 12.7 μmol/L (mildly elevated, normal <10-12) may reflect B-vitamin deficiency or early renal dysfunction

Recommended Diagnostic Workup

Obtain the following tests immediately to confirm the diagnosis and guide treatment:

• Intact parathyroid hormone (PTH): Expected to be elevated (>65-70 pg/mL) confirming secondary hyperparathyroidism 2, 1
• Serum phosphorus: May be low-normal or low due to PTH-mediated phosphate wasting 2
• Alkaline phosphatase: Likely elevated, indicating increased bone turnover 2
• Ionized calcium: More accurate assessment of calcium status than total calcium 4
• Estimated GFR (eGFR): To stage any CKD and guide vitamin D dosing 2
• Urinary calcium excretion: To assess for relative hypercalciuria before initiating treatment 1
• Arterial blood gas or venous blood gas: To confirm metabolic acidosis and assess severity 2

Treatment Algorithm

Step 1: Address Metabolic Acidosis

Initiate oral sodium bicarbonate supplementation to maintain serum bicarbonate within normal range (22-26 mmol/L) 2:

• Start with 650-1300 mg (approximately 8-15 mEq) three times daily
• Metabolic acidosis independently worsens bone disease and must be corrected before vitamin D therapy will be fully effective 2

Step 2: Vitamin D Repletion

Since vitamin D is 33 ng/mL (borderline insufficient) and PTH is likely elevated, initiate ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) supplementation 2, 1:

• For vitamin D levels 16-30 ng/mL: Ergocalciferol 50,000 IU weekly for 8-12 weeks, then monthly maintenance 2
• Alternative daily dosing: Cholecalciferol 2,000 IU daily for 12 weeks, then 1,000-2,000 IU daily 2
• Target 25-hydroxyvitamin D level >32 ng/mL, ideally 40-50 ng/mL 2

Step 3: Calcium Supplementation

Provide elemental calcium 1,000-1,500 mg daily in divided doses 2, 1:

• Calcium carbonate 500-600 mg elemental calcium twice daily with meals (requires acid for absorption)
• If malabsorption suspected or achlorhydria present, use calcium citrate instead 1
• Total elemental calcium intake (diet + supplements) should not exceed 2,000 mg/day 2

Step 4: Monitoring Protocol

Measure serum calcium and phosphorus at 1 month after initiating therapy, then every 3 months 2, 1:

• If corrected total calcium exceeds 10.2 mg/dL, reduce or discontinue calcium supplements and vitamin D 2
• Recheck 25-hydroxyvitamin D at end of repletion period (8-12 weeks) to ensure adequate levels 2
• Once replete, continue maintenance vitamin D supplementation and reassess 25-hydroxyvitamin D annually 2, 1

Critical Pitfalls to Avoid

Do not initiate bisphosphonate therapy if osteoporosis is suspected until vitamin D deficiency is corrected—vitamin D deficiency attenuates bisphosphonate efficacy and increases risk of severe hypocalcemia 2

Avoid excessive calcium supplementation without monitoring—this can lead to hypercalcemia, hypercalciuria, nephrolithiasis, and vascular calcification, particularly if PTH remains elevated 2, 1

Do not overlook the metabolic acidosis—failure to correct acidosis will limit the effectiveness of vitamin D and calcium therapy, as acidosis promotes continued bone mineral dissolution 2

If eGFR is <45 mL/min/1.73m² (CKD stage 3b or worse), standard vitamin D supplementation may be insufficient—these patients may require active vitamin D sterols (calcitriol, paricalcitol) rather than ergocalciferol alone 2

Prognosis with Treatment

With appropriate vitamin D repletion, calcium supplementation, and correction of metabolic acidosis, expect significant improvement in symptoms within 8-12 weeks 3:

• Muscle weakness and fatigue typically improve within 4-8 weeks
• Bone pain may take longer to resolve (3-6 months) as bone mineralization normalizes
• PTH levels should decrease toward normal range with successful treatment 1, 3