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Vitamin D Deficiency & Osteomalacia (Clinical)

Name: Vitamin D Deficiency & Osteomalacia (Clinical)
Creator: Veli Bakalov, MD

Soft bones, abnormal labs — replete first, then think phosphate

Endocrinology·Bone & Reproductive Endocrinology·4 min read·8 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Measure 25-hydroxyvitamin D, not 1,25-(OH)2D, to assess stores; deficiency is <20 ng/mL.
Test only at-risk patients: malabsorption (celiac, bariatric surgery, IBD), CKD or liver disease, anticonvulsants or glucocorticoids, limited sun, institutionalized elderly.
Vitamin D deficiency raises PTH, which keeps calcium near normal but wastes phosphate, leaving osteoid unmineralized.
Osteomalacia: diffuse bone pain, proximal weakness, waddling gait, and Looser zones (pseudofractures).
Osteomalacia labs: low or low-normal calcium, low phosphate, high ALP, high PTH, low urine calcium; osteoporosis labs are normal.
Replete with D3 or D2 50,000 IU weekly for 8 weeks, then maintenance plus calcium, before any bisphosphonate; calcitriol only when 1α-hydroxylation is impaired (advanced CKD).
FGF23 excess causes phosphate wasting with normal 25-OH D: resect a tumor-induced osteomalacia tumor; burosumab for X-linked hypophosphatemia.
Tenofovir disoproxil can cause Fanconi syndrome with hypophosphatemic osteomalacia: switch the drug.

Testing vitamin D status

The right metabolite. Serum 25-hydroxyvitamin D, with a half-life of about 2–3 weeks, reflects both dietary intake and skin synthesis and is the test of vitamin D stores. Deficiency is a level below 20 ng/mL (50 nmol/L); osteomalacia usually reflects severe, prolonged deficiency, often below 10 ng/mL. The active hormone, 1,25-(OH)₂D, is a poor screen: PTH stimulates renal 1α-hydroxylase, so it is often normal or even high in deficiency. Reserve it for CKD, granulomatous hypercalcemia such as sarcoidosis, and inherited hypophosphatemic or vitamin D–dependent disorders.

Whom to test. Routine screening of healthy adults is not recommended. Test patients at risk:

Malabsorption: celiac disease, bariatric surgery (especially Roux-en-Y bypass), inflammatory bowel disease.
CKD or liver disease.
Drugs: anticonvulsants (phenytoin, phenobarbital, carbamazepine) and glucocorticoids.
Limited sun exposure and institutionalized or homebound elderly (dark skin or obesity alone is not a reason for routine testing).
Osteoporosis or unexplained bone pain, weakness, or high alkaline phosphatase.

From deficiency to osteomalacia

Mechanism. Without vitamin D, the gut absorbs less calcium and phosphate. Secondary hyperparathyroidism restores serum calcium through bone resorption and renal calcium reabsorption but causes phosphaturia. The resulting low calcium-phosphate product leaves newly laid osteoid unmineralized: osteomalacia in adults, rickets in children with open growth plates (bowed legs, rachitic rosary, widened wrists, delayed walking). Breast milk is low in vitamin D, so the AAP recommends 400 IU of vitamin D daily for breastfed and partially breastfed infants, starting in the first days of life.

Presentation. Diffuse bone pain and tenderness (elicited by pressing on the sternum or tibia), proximal muscle weakness with a waddling gait, and fractures after minimal trauma. The picture is often mistaken for fibromyalgia or polymyalgia.

Imaging. Looser zones (pseudofractures) are narrow radiolucent bands perpendicular to the cortex at the femoral neck, pubic rami, ribs, and lateral scapular border. DXA shows low BMD but cannot distinguish osteomalacia from osteoporosis; bone biopsy with tetracycline labeling (widened osteoid seams, delayed mineralization) is definitive but rarely needed.

Laboratory patterns

Test	Vitamin D–deficient osteomalacia	FGF23-mediated osteomalacia	Osteoporosis
Calcium	Low or low-normal	Normal	Normal
Phosphate	Low	Very low, with high urine phosphate	Normal
Alkaline phosphatase	High	High	Normal
PTH	High	Normal or mildly high	Normal
25-OH D	Low	Normal	Normal
1,25-(OH)₂D	Normal, low, or high	Low or inappropriately normal	Normal
Urine calcium	Low	Normal or low	Normal

Treatment

Repletion. Give cholecalciferol (D3) or ergocalciferol (D2) 50,000 IU weekly for 8 weeks (or about 6,000 IU daily), then 1,000–2,000 IU daily for maintenance, with adequate calcium (about 1,000–1,200 mg/day). Recheck 25-OH D after about 3 months. Malabsorption, including after bariatric surgery, often requires higher doses. Bone pain and weakness improve over weeks; alkaline phosphatase may rise transiently as healing begins, then falls over months.

Replete vitamin D and calcium before starting a bisphosphonate. Otherwise hypocalcemia can follow, and the mineralization defect persists.

Calcitriol. When 1α-hydroxylation fails (advanced CKD, especially dialysis with secondary hyperparathyroidism; hypoparathyroidism; inherited 1α-hydroxylase deficiency), give calcitriol or an active analog, because nutritional vitamin D cannot be activated. Calcitriol does not refill 25-OH D stores and can cause hypercalcemia, so monitor calcium.

Phosphate-wasting osteomalacia

FGF23 excess. FGF23 blocks renal phosphate reabsorption and suppresses 1α-hydroxylase. The result is very low phosphate with high urine phosphate, low or inappropriately normal 1,25-(OH)₂D, and normal calcium and 25-OH D.

Tumor-induced osteomalacia. Adult-onset hypophosphatemic osteomalacia with high FGF23 and no family history suggests a small phosphaturic mesenchymal tumor in bone or soft tissue. Whole-body somatostatin-receptor imaging (Ga-68 DOTATATE PET/CT) locates it, and complete resection is curative. If it cannot be found or removed, treat with phosphate plus calcitriol or with burosumab.

X-linked hypophosphatemia. A PHEX mutation (X-linked dominant) causes lifelong FGF23-driven phosphate wasting: childhood rickets with bowed legs and short stature, dental abscesses, and adult osteomalacia with enthesopathy. Burosumab, an anti-FGF23 monoclonal antibody, raises phosphate and heals rickets better than conventional phosphate plus calcitriol.

Fanconi syndrome. Proximal tubular injury wastes phosphate along with glucose (glycosuria despite normal serum glucose), amino acids, bicarbonate (proximal RTA), and urate. Tenofovir disoproxil fumarate is a classic cause; switch to tenofovir alafenamide or another agent. Myeloma light chains and ifosfamide cause the same pattern.