Alkaline Phosphatase in Severe Osteoporosis
Alkaline phosphatase (ALP) does not typically increase with severe osteoporosis itself; rather, it remains normal or may even be low, but can become elevated during treatment with anabolic agents like teriparatide, or may be elevated in postmenopausal osteoporosis with high bone turnover. 1, 2
Baseline ALP Levels in Osteoporosis
In untreated severe osteoporosis, serum calcium, phosphorus, and alkaline phosphatase are typically within normal range in almost all patients. 2
Postmenopausal osteoporosis with high bone turnover may show somewhat elevated bone-specific alkaline phosphatase (B-ALP) in some patients, but this is not universal. 2
Elevated ALP in postmenopausal women is primarily caused by high bone turnover rather than the severity of osteoporosis itself. 1
Before treatment, bone-specific ALP values in postmenopausal women with osteoporosis are generally within the postmenopausal reference ranges. 3
Clinical Significance of Low ALP in Osteoporosis
A persistently low ALP (<30 IU/L) in osteoporosis patients should raise suspicion for hypophosphatasia (HPP), a condition that can be mistaken for osteoporosis and is a contraindication to antiresorptive therapy. 4
Low ALP occurs in approximately 9% of patients attending osteoporosis clinics, with 0.4% having persistently low levels. 4
Hypophosphatasia was diagnosed in 3% of osteoporosis clinic patients with low ALP, making this a critical screening tool. 4
The American Association of Clinical Endocrinologists recommends referral to an osteoporosis specialist for patients with unexplained low ALP levels, particularly with features such as premature tooth loss, stress fractures, or atypical fractures. 5
Patients with suspected HPP should not be initiated on bisphosphonates or denosumab, as these can worsen the condition. 5
ALP Changes During Osteoporosis Treatment
With Antiresorptive Therapy (Bisphosphonates)
Bisphosphonate treatment (alendronate, risedronate) produces a significant decrease in ALP after 3 months, reaching a plateau after 6 months, with mean changes of -19% to -34%. 3, 1
The decrease in ALP with bisphosphonate therapy is strongly correlated with decreased bone-specific ALP, confirming that elevated ALP in postmenopausal women is mainly caused by high bone turnover. 1
This reduction in ALP serves as a marker of suppression of bone turnover, though it does not predict individual bone mineral density response to therapy. 3
With Anabolic Therapy (Teriparatide)
Teriparatide (PTH analog) can cause asymptomatic elevation in alkaline phosphatase as a side effect during treatment of severe osteoporosis. 6
This elevation reflects increased bone formation activity, which is the intended mechanism of action for anabolic agents. 6
Diagnostic Approach When ALP is Elevated
Measure bone-specific alkaline phosphatase (B-ALP) directly rather than relying on total ALP alone, as this provides superior diagnostic accuracy for bone disease. 7
Check serum calcium, phosphate, and PTH levels to evaluate for metabolic bone disorders. 7
Consider measuring 25-hydroxyvitamin D to evaluate for vitamin D deficiency, which can cause elevated ALP through secondary hyperparathyroidism. 7
If GGT is normal with elevated ALP, this confirms bone origin rather than hepatobiliary disease. 8
Important Clinical Pitfalls
Do not assume severe osteoporosis automatically means elevated ALP—this is a common misconception. 2
Always investigate persistently low ALP (<30 IU/L) before initiating antiresorptive therapy, as hypophosphatasia may be present and would be worsened by bisphosphonates or denosumab. 5, 4
Neither baseline B-ALP nor the percent change in B-ALP after treatment correlates with bone mineral density changes, so ALP should not be used to predict treatment response. 3
In patients on teriparatide, expect ALP elevation as a normal pharmacologic effect rather than a pathologic finding. 6