What are the next steps and likely diagnosis for a patient with gradual onset of extremity and hip pain, now unable to walk, with normal Complete Blood Count (CBC), normal Comprehensive Metabolic Panel (CMP), urine, and thyroid tests, but significantly elevated alkaline phosphatase level?

Likely Diagnosis: Paget's Disease of Bone

The most likely diagnosis is Paget's disease of bone, given the markedly elevated alkaline phosphatase (600 U/L), gradual onset of extremity and hip pain, and progressive functional impairment leading to inability to walk. 1, 2

Immediate Next Steps

Confirm Bone Origin of Alkaline Phosphatase

• Measure bone-specific alkaline phosphatase (B-ALP) to confirm the bone origin of the elevation, as this is more specific than total ALP 1
• Measure gamma-glutamyl transferase (GGT) - if GGT is normal, this strongly indicates a non-hepatic (bone) source of ALP elevation 1, 2
• Obtain liver function tests to definitively exclude hepatobiliary causes 2

Essential Laboratory Work-Up

• Measure serum calcium, phosphate, and parathyroid hormone (PTH) levels to evaluate for metabolic bone disorders 1
• Check 25-hydroxyvitamin D levels to assess for vitamin D-related bone disease 1
• Obtain complete metabolic panel including renal function 1

Primary Imaging Studies

• Bone scintigraphy (bone scan) is the primary recommended imaging modality for elevated bone ALP, particularly when evaluating the extent of disease 1
• Obtain targeted radiographs of symptomatic areas (extremities and hips) to look for characteristic findings of Paget's disease including cortical thickening, coarsened trabecular pattern, and bone expansion 1

Differential Diagnosis to Consider

Paget's Disease of Bone (Most Likely)

• Typically presents with gradual onset bone pain, elevated alkaline phosphatase (often >500 U/L), and progressive functional impairment 3
• Alkaline phosphatase levels at least twice the upper limit of normal are characteristic 3
• Affects middle-aged and older adults, commonly involving the pelvis, spine, femur, and skull 3

Metastatic Bone Disease (Critical to Exclude)

• Metastatic disease accounts for a significant portion of isolated elevated ALP cases, with common primary tumors including breast, prostate, renal cell carcinoma, and gastric cancer 1
• In one study, 57% of patients with isolated elevated ALP of unclear etiology had underlying malignancy, with 52 having bony metastasis 4
• Bone scan is essential to evaluate for metastatic disease 1, 2

Metabolic Bone Disease (Less Likely Given Age)

• X-linked hypophosphatemia presents with elevated ALP, hypophosphatemia, and renal phosphate wasting 1
• However, this typically presents in childhood rather than with gradual adult-onset symptoms 5

Osteomalacia/Vitamin D Deficiency

• Can present with bone pain, elevated ALP, and functional impairment 1
• Check 25-hydroxyvitamin D levels to evaluate this possibility 1

Treatment Approach if Paget's Disease Confirmed

Initial Treatment

• The recommended treatment regimen for Paget's disease is alendronate 40 mg once daily for six months 3
• Alendronate must be taken at least 30 minutes before the first food, beverage, or medication of the day with plain water only 3
• Patient should remain upright for at least 30 minutes after taking medication to reduce esophageal irritation risk 3

Monitoring Response

• Re-treatment may be considered following a six-month post-treatment evaluation period in patients who have relapsed, based on increases in serum alkaline phosphatase, which should be measured periodically 3
• Re-treatment may also be considered in those who failed to normalize their serum alkaline phosphatase 3
• In clinical trials, approximately 85% of patients treated with alendronate 40 mg/day achieved response (normalization of serum alkaline phosphatase or decrease ≥60% from baseline) 3

Calcium and Vitamin D Supplementation

• Instruct patient to take supplemental calcium if dietary intake is inadequate 3
• Patients at increased risk for vitamin D insufficiency may need vitamin D supplementation 3

Critical Pitfalls to Avoid

• Do not assume hepatobiliary disease without measuring GGT or bone-specific ALP - normal GGT with elevated total ALP strongly suggests bone origin 1, 2
• Do not delay bone scan if malignancy is suspected - metastatic bone disease is a common cause of markedly elevated ALP and requires urgent evaluation 1, 4
• Do not overlook the possibility of multiple myeloma or other hematologic malignancies - though less common, these can present with bone pain and elevated ALP 4
• In patients with confirmed Paget's disease, failure to provide adequate calcium and vitamin D supplementation can compromise treatment efficacy 3