Osteomalacia

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Bone quantity may be reduced in both osteoporosis and osteomalacia, but osteomalacia leaves osteoid insufficiently mineralised. Ask about diffuse rib, pelvic, hip or foot pain; rising from a chair, stairs, falls and fractures; sunlight, skin pigmentation, clothing, diet and supplements; diarrhoea, bariatric or intestinal surgery; kidney or liver disease; dental history; and anticonvulsant, tenofovir or iron-infusion exposure. Examine gait, proximal power, bone tenderness, deformity and signs of malabsorption or tubular dysfunction.

Interpret tests physiologically rather than treating a vitamin-D number in isolation. Nutritional deficiency commonly lowers 25-hydroxyvitamin D and phosphate while raising ALP and PTH, but calcium may remain in range until advanced disease. In CKD, eGFR, phosphate, PTH and ALP reflect CKD-mineral bone disorder. In isolated hypophosphataemia, urinary handling distinguishes appropriate renal conservation from FGF23-mediated or proximal-tubular loss. A low DXA result is nonspecific and can lead to unsafe antiresorptive treatment if mineralisation failure is missed.

Treatment follows cause. Nutritional deficiency generally responds to oral colecalciferol loading, maintenance and sufficient dietary calcium; malabsorption may need supervised higher or alternative regimens. Active vitamin-D analogues and oral phosphate require specialist monitoring. Search for a phosphaturic tumour when acquired FGF23-mediated wasting is unexplained; complete resection can cure it. Follow symptoms, mineral indices and ALP until recovery is sustained, recognising that ALP may take months to normalise.

Key points

Osteomalacia is failure to mineralise newly formed adult osteoid; suspect it with diffuse bone tenderness, proximal weakness, waddling gait, insufficiency fractures or Looser pseudofractures.
The common nutritional pattern is low 25-hydroxyvitamin D, raised ALP, raised PTH and low phosphate; adjusted calcium may be low or preserved by secondary hyperparathyroidism.
Request adjusted calcium, phosphate, ALP, PTH, vitamin D, magnesium, renal and liver profiles first, then distinguish substrate deficiency, CKD and phosphate wasting.
If phosphate remains low, paired fasting blood and urine measurements with fractional excretion or TmP/GFR determine whether the kidney is inappropriately wasting phosphate.
Treat nutritional deficiency with a total colecalciferol loading dose near 300,000 units over six to ten weeks, then 800–2,000 units daily maintenance, ensuring adequate calcium intake.
Check adjusted calcium about one month after loading or earlier when high risk; investigate rather than repeatedly loading if vitamin D, ALP, phosphate or symptoms fail to improve.
Do not give routine calcitriol for ordinary nutritional deficiency; CKD, hypoparathyroidism and phosphate-wasting disorders need specialist cause-specific plans.
Correct osteomalacia before potent antiresorption because denosumab or intravenous bisphosphonate can precipitate serious hypocalcaemia when mineral substrate is inadequate.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Vitamin-D substrate deficiency

Low sunlight, deeply pigmented skin, covering clothing, limited diet, frailty, obesity and malabsorption reduce vitamin-D availability; liver disease or enzyme-inducing medicines may impair handling.

Renal mineral disease

Advanced chronic kidney disease reduces calcitriol production and phosphate excretion, driving secondary hyperparathyroidism and mixed renal bone disease rather than simple nutritional deficiency.

Phosphate wasting

FGF23-mediated inherited disease or mesenchymal tumours, and proximal tubular disorders such as Fanconi syndrome, cause inappropriate urinary phosphate loss despite hypophosphataemia.

Medicine and rare causes

Anticonvulsants, tenofovir, repeated ferric carboxymaltose and aluminium can contribute; hypophosphatasia instead has low alkaline phosphatase and must not be mislabelled.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Unmineralised osteoid
Osteoblasts produce collagenous osteoid, but inadequate calcium-phosphate product or mineralisation defects prevent hydroxyapatite deposition, leaving mechanically soft bone.
2
Secondary hyperparathyroidism
Vitamin-D deficiency reduces intestinal calcium absorption; PTH preserves serum calcium by increasing turnover and renal phosphate loss, so calcium may remain normal while phosphate falls.
3
Remodelling and ALP rise
Increased osteoblastic effort raises alkaline phosphatase, while newly formed matrix remains inadequately mineralised, producing diffuse pain, microfractures and pseudofractures.
4
Muscle dysfunction
Vitamin-D and phosphate depletion impair proximal muscle performance and postural control, causing difficulty rising or climbing stairs and adding falls to skeletal vulnerability.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Diffuse skeletal pain

Poorly localised rib, pelvic, hip, lumbar or foot pain and bony tenderness are typical, unlike isolated joint-line pain.

Proximal myopathy

Difficulty rising without arm support, climbing stairs or lifting, with waddling gait but preserved sensation, suggests mineral-related muscle dysfunction.

Pseudofracture pattern

Looser zones are transverse incomplete radiolucent lines with sclerotic margins, often symmetrical at femoral necks, pubic rami, ribs or scapulae.

Nutritional-risk phenotype

Housebound status, little skin exposure, dark skin, restrictive diet without supplementation, frailty or malabsorptive surgery increases deficiency probability.

Phosphate-wasting clues

Childhood short stature or deformity suggests inherited disease; adult-onset fractures with severe low phosphate can indicate an FGF23-secreting tumour.

Fanconi pattern

Glycosuria despite normal blood glucose, aminoaciduria, bicarbonate loss, hypokalaemia and low urate accompany generalised proximal tubular phosphate wasting.

Red flags requiring action

Perioral tingling, carpopedal spasm, seizure, laryngospasm or arrhythmia with low calcium requires monitored emergency replacement rather than an outpatient vitamin-D course.
Sudden focal pain, deformity or inability to bear weight may indicate an insufficiency fracture through poorly mineralised bone and needs urgent imaging and protection.
Severe persistent hypophosphataemia with weakness, respiratory compromise, haemolysis or rhabdomyolysis needs acute correction and cause-directed inpatient assessment.
Weight loss, anaemia, gastrointestinal symptoms, renal tubular abnormalities or a focal tumour syndrome suggests malabsorption, Fanconi syndrome or oncogenic phosphate wasting.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line mineral profileFirst stepFirst line
Why
Identify the biochemical mineralisation pattern and kidney, liver or magnesium contributions before replacement.
Interpretation and limitations
Measure adjusted calcium, phosphate, ALP, PTH, vitamin D, magnesium, eGFR and liver tests together; raised ALP needs hepatic-source distinction.
02
Fasting urine phosphate handling
Why
Separate reduced intake or redistribution from inappropriate renal phosphate loss.
Interpretation and limitations
Calculate fractional phosphate excretion or TmP/GFR from paired fasting urine and plasma; failure to conserve during low serum phosphate supports renal wasting.
03
Cause-directed malabsorption screen
Why
Find coeliac, pancreatic or intestinal disease when oral substrate is not absorbed.
Interpretation and limitations
Use coeliac serology with total IgA, FBC, ferritin, folate and B12, then directed gastroenterology tests; negative serology is unreliable in IgA deficiency.
04
Plain radiography of painful sites
Why
Detect Looser zones, complete insufficiency fracture, deformity or a focal destructive alternative.
Interpretation and limitations
Pseudofractures support advanced disease but may be absent; persistent inability to bear weight can require MRI despite a normal radiograph.
05
FGF23 and tumour localisation
Why
Confirm and localise acquired FGF23-mediated wasting after renal loss has been demonstrated.
Interpretation and limitations
Inappropriately normal or high intact FGF23 during hypophosphataemia supports the mechanism; specialist functional imaging and targeted CT or MRI seek a small tumour.
06
Reference bone histomorphometry
Why
Directly demonstrate delayed mineralisation when non-invasive results remain discordant and treatment would change.
Interpretation and limitations
Double tetracycline-labelled iliac-crest biopsy quantifies osteoid and mineralisation lag, but is invasive and reserved for specialist uncertainty.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Osteoporosis

Osteoporosis reduces the amount and architecture of normally mineralised bone and usually leaves calcium, phosphate and ALP normal; DXA alone cannot distinguish it.

Inflammatory or muscle disease

Polymyalgia, inflammatory myopathy, hypothyroidism and neurological weakness resemble proximal disability; CK, inflammatory markers, thyroid tests and examination localise the process.

Paget or malignant disease

Paget disease causes focal high-turnover lesions, while metastasis or myeloma causes destructive pain; imaging distribution and complete biochemical pattern separate them.

Hypophosphatasia

Adult hypophosphatasia can cause stress fractures, early tooth loss and pain but has persistently low ALP; bisphosphonates may be harmful if it is mistaken for osteoporosis.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01First-line diagnosisRead the mineral pattern togetherFirst stepFirst lineDiffuse pain, proximal weakness, low-trauma fracture or unexpectedly low density raises a mineralisation concern.

1Obtain mineral, renal, liver, magnesium, PTH and vitamin-D tests before high-dose replacement when clinical stability permits.
2Identify urgent hypocalcaemia, critical phosphate depletion or fracture, then separate common vitamin-D deficiency from CKD and isolated renal phosphate wasting.
3Use targeted coeliac, endocrine, medicine, tubular and malignant investigations rather than assuming every low vitamin-D result explains the phenotype.
4Image focal or weight-bearing pain and protect a suspected insufficiency fracture while advanced imaging or orthopaedic review is arranged.

02Nutritional treatmentRestore vitamin D and calciumThe pattern supports nutritional vitamin-D deficiency without severe acute hypocalcaemia.

1Give an oral colecalciferol loading course totalling approximately 300,000 units over six to ten weeks using an accepted schedule the patient can follow.
2Ensure adequate dietary or supplemental calcium because vitamin-D loading alone can expose calcium deficit and delay remineralisation.
3Continue colecalciferol 800–2,000 units daily after loading while risk persists and address sunlight, diet, malabsorption and causative medicines.
4Recheck calcium around one month, then follow phosphate, ALP, PTH, strength and pain; reassess adherence and diagnosis if recovery is incomplete.

03Specialist alternativeTreat renal or phosphate-wasting diseaseAlternativeAdvanced CKD, inappropriate urinary phosphate loss, inherited features or persistent disease despite adequate nutritional replacement is present.

1Refer CKD-related disease to nephrology for integrated phosphate, PTH, calcium and turnover management; never use calcitriol as routine nutritional replacement.
2For FGF23 or tubular loss, use metabolic-bone specialists to balance divided phosphate with active vitamin D while monitoring urine calcium, nephrocalcinosis and secondary hyperparathyroidism.
3Localise and resect an FGF23-secreting tumour when possible; consider commissioned burosumab for eligible inherited or unresectable FGF23-mediated disease.
4Correct causative drug exposure collaboratively, particularly tenofovir tubular toxicity or recurrent iron-associated hypophosphataemia.

04Emergency correctionStabilise symptomatic mineral failureTetany, seizure, ECG abnormality, arrhythmia, respiratory weakness or severe fracture accompanies major depletion.

1Use cardiac monitoring, repeat calcium, phosphate, magnesium, potassium and renal measurements, and treat concurrent magnesium depletion.
2Give intravenous calcium gluconate for symptomatic hypocalcaemia according to the hospital protocol, adjusting infusion to symptoms, ECG and serial calcium.
3Replace severe symptomatic phosphate cautiously by a renal-adjusted intravenous protocol with frequent mineral review, then move to cause-specific oral treatment.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

Restores substrate in nutritional vitamin-D deficiency when absorption and kidney activation are adequate.

Colecalciferol loading

Give a total near 300,000 units orally over six to ten weeks; a common regimen is 50,000 units once weekly for six weeks, followed immediately by maintenance.

Check adjusted calcium and renal function. Use specialist advice in granulomatous disease, lymphoma, hyperparathyroidism, stones, severe CKD, complex pregnancy or malabsorption; avoid duplicated supplements.

Prevents recurrence after correction and supplies vitamin D during ongoing low exposure or malabsorptive risk.

Colecalciferol maintenance

Use 800–2,000 units orally once daily after loading while risk persists; higher maintenance in malabsorption or selected obesity needs clinical and biochemical supervision.

Review over-the-counter preparations and calcium intake. Hypercalcaemia or hypercalciuria suggests excess or another mechanism; recommended maintenance is generally compatible with pregnancy.

Provides calcium during remineralisation when dietary intake is inadequate or hypocalcaemia coexists.

Calcium carbonate

Supplement only the dietary shortfall, commonly 500 mg elemental calcium orally once or twice daily with food in divided doses, aiming for roughly 700–1,200 mg total daily intake.

May cause constipation, stones and hypercalcaemia. Separate from levothyroxine, iron, tetracyclines and quinolones; use monitored exposure in CKD and avoid calcium loading in hypercalcaemia.

Active vitamin-D treatment for selected hypoparathyroid, advanced renal or phosphate-wasting states.

Calcitriol

Specialists commonly start 0.25 micrograms orally once daily and titrate at two-to-four-week intervals to calcium, phosphate, PTH and indication; nutritional deficiency alone does not require it.

Hypercalcaemia and hypercalciuria can develop rapidly; monitor minerals, kidney function and urine calcium, avoid uncoordinated supplements and obtain specialist pregnancy advice.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Insufficiency fractures

Looser zones and complete fractures occur in ribs, pubic rami, femoral neck, subtrochanteric femur and metatarsals, sometimes bilaterally or at multiple stages.

Falls and immobility

Proximal weakness, waddling gait and pain impair transfers and balance, leading to falls, deconditioning, dependency and complications of immobility.

Persistent deformity

Longstanding severe disease may cause kyphosis, pelvic or long-bone deformity and permanent mechanical disability even after mineralisation improves.

Replacement toxicity

Excess calcium or active vitamin D causes hypercalcaemia, hypercalciuria, stones and kidney injury; rapid phosphate therapy can cause hypocalcaemia and ectopic calcification.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Recheck adjusted calcium around one month after loading, sooner with symptoms, renal impairment, hyperparathyroidism, granulomatous disease or active-vitamin-D treatment.
Follow phosphate and ALP alongside pain, tenderness, proximal strength and gait; ALP can remain raised during healing and should trend over months.
If vitamin D stays low, examine adherence, formulation, interactions and malabsorption before serial high-dose courses.
During phosphate or calcitriol treatment, monitor calcium, phosphate, PTH, renal function and urine calcium, with renal ultrasound when nephrocalcinosis risk warrants.
Repeat imaging for persistent focal or weight-bearing pain and guide return to loading after an insufficiency fracture.
Reconsider diagnosis when vitamin D corrects but low phosphate, raised ALP, weakness or fractures persist.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Calcium may look normal

Secondary hyperparathyroidism can defend serum calcium at the cost of skeletal mineral and urinary phosphate loss, so normal calcium does not exclude severe disease.

ALP direction matters

Raised ALP supports active osteomalacia after hepatic disease is excluded; persistently low ALP points away and raises hypophosphatasia.

DXA measures quantity

Low areal density occurs in both deficient mineralisation and osteoporosis; biochemistry and context must be resolved before antiresorptive treatment.

Urine reveals mechanism

A healthy kidney should conserve phosphate during hypophosphataemia; continued urinary loss identifies a tubular or FGF23-mediated process.

Recovery takes time

Biochemical substrate improves before skeletal strength and muscle confidence fully recover; rehabilitation and fracture protection remain important during remineralisation.

11Common pitfallsFrequent interpretation and management errors.

01
Do not diagnose osteoporosis from DXA alone when diffuse pain, proximal weakness or abnormal phosphate and ALP suggest a mineralisation disorder.
02
Do not use serum calcium as a substitute for vitamin D, phosphate, PTH and ALP; compensation can conceal substrate deficiency.
03
Do not treat persistent hypophosphataemia with vitamin D alone without checking urinary loss, medicines, Fanconi features and FGF23 disease.
04
Do not prescribe calcitriol as a stronger routine vitamin D; it bypasses regulation and can rapidly cause hypercalcaemia.
05
Do not begin denosumab or intravenous bisphosphonate while clinically important hypocalcaemia or osteomalacia remains uncorrected.
06
Do not attribute failure to improve solely to non-adherence; malabsorption, wrong mechanism, fracture or phosphaturic tumour may need detection.