Hypophosphatasia
The anchor question: is this persistently low alkaline phosphatase hypophosphatasia, in an adult with stress fractures, chronic pain or early tooth loss who is about to start a bisphosphonate? Low ALP is the clue, and it sits on a routine metabolic panel. The diagnosis is often missed or delayed, particularly in adults; across all ages in the global registry, the median time from symptoms to diagnosis is 5.7 years.1
Who this cohort covers
Adults with an ALP persistently low for age and sex and no other identifiable cause, plus the features the HPP International Working Group uses as diagnostic criteria. Major: a pathogenic or likely pathogenic ALPL variant, elevated natural substrates, atypical femoral fractures (pseudofractures), recurrent metatarsal fractures. Minor: poorly healing fractures, chronic musculoskeletal pain, early atraumatic tooth loss, chondrocalcinosis, nephrocalcinosis. Two major criteria, or one major and two minor, make the diagnosis.1
It also covers the related disorders of mineralization that turn up in the same clinic. X-linked hypophosphatemia in adults: bone and joint pain, fractures and pseudofractures, early joint damage, enthesopathy, poor dental health and hearing loss, on a persistently low fasting serum phosphorus. The adult guideline asks us to exclude the other causes of renal phosphate wasting before calling it XLH, tumor-induced osteomalacia and intravenous iron among them.2
Low ALP is worth chasing. In a 2026 systematic review, studies at low risk of bias found genetically confirmed HPP in 10.4 to 26.2% of patients with persistently low ALP in general clinical populations, 46.4 to 56.5% in rheumatology populations and 57.1 to 87.5% in osteoporosis populations.3 Low ALP also has ordinary causes, and the working group lists them: antiresorptive therapy, excess vitamin D, chemotherapy, hypothyroidism, hypoparathyroidism, hypercortisolism, myeloma, celiac disease, deficiencies of magnesium, zinc, vitamin C or protein and calories, severe illness or surgery, Wilson disease, and blood drawn into an EDTA or citrate tube.1
The bisphosphonate caution. Bisphosphonates are pyrophosphate analogues, and the first reported adult with HPP and atypical subtrochanteric femoral fractures had four years of alendronate and then zoledronate.4 GeneReviews lists bisphosphonates, denosumab and excess vitamin D as agents to avoid in HPP, and the working group warns that bisphosphonates may further impair mineralization and raise the risk of atypical femoral fractures.5 1 The evidence is case reports and expert consensus; a small case-control study found no ALPL coding variants in ten patients with atypical femur fractures.6 We act on the caution anyway, because checking costs an ALP history and a PLP level.
Care map
| Role | Year 1, Establish | Year 2, Treat | Year 3, Sustain |
|---|---|---|---|
| Anchor | Pull every ALP on record and compare each with the age- and sex-specific range. Work through the acquired causes of a low value, including an antiresorptive the patient may already be taking.1 Hold the bisphosphonate or denosumab decision until HPP is excluded.5 Fracture, dental and pain history; three-generation pedigree for fractures, early tooth loss, bowed legs and low phosphate. | Hold the metabolic bone plan together. Keep bisphosphonates and denosumab off the list once HPP is confirmed.5 Coordinate burosumab or conventional therapy for XLH with the treating specialist. | Annual review of fractures, pain, function and dental status. Revisit the diagnosis if the picture changes. |
| Genetics | ALPL sequencing; a pathogenic or likely pathogenic variant is a major criterion.1 Heterozygous variants usually give milder disease, and adult HPP can be inherited as dominant or recessive.5 For low phosphate, a hypophosphatemia gene panel that includes PHEX; a PHEX variant confirms XLH but is not required for the diagnosis.2 | Cascade testing: relatives at risk once the familial ALPL variant is known;5 in XLH, first-degree relatives by molecular or biochemical testing.7 | Reclassification check on any ALPL variant of uncertain significance. |
| Specialists | Endocrinology or a metabolic bone specialist to confirm and plan. Dentistry from the start: early atraumatic tooth loss is a criterion,1 and dental care is part of management.5 | HPP: asfotase alfa is the targeted therapy.5 Its adult trial data come from pediatric-onset HPP, with falling substrate levels and a longer 6-minute walk over five years.8 For adult-onset disease the evidence is thin, and the decision sits with the metabolic bone specialist. Teriparatide for adult osteomalacia: limited experience.5 Orthopedics for internal fixation of pseudofractures and stress fractures.5 XLH: burosumab is recommended over no therapy in adults with fractures or pseudofractures, and suggested over conventional phosphate and active vitamin D otherwise.2 In the adult phase 3 trial, 94.1% on burosumab reached a normal serum phosphate (placebo, 7.6%), and 43.1% of active fractures had healed by week 24 (placebo, 7.7%).9 | Follow-up per involvement, at the interval the treating specialist sets. |
| Diagnostics | HPP: repeat ALP; plasma PLP (vitamin B6) after a week off pyridoxine; calcium, phosphate, PTH and 25-hydroxyvitamin D for the biochemical profile; imaging of painful sites for pseudofractures and metatarsal fractures, both criteria.1 XLH: fasting serum phosphorus, TmP/GFR, calcium, ALP, PTH, 25-hydroxyvitamin D, creatinine and urine calcium; a skeletal survey for asymptomatic pseudofractures; baseline bone density and dental imaging.2 | On burosumab: serum phosphate, calcium, creatinine, ALP and PTH.7 On asfotase alfa: PLP and the 6-minute walk, the trial's end points.8 | HPP: renal ultrasound yearly, nephrology as needed.5 XLH on conventional therapy: urine calcium and periodic renal ultrasound for nephrocalcinosis.7 |
| Therapies | Physical medicine, physical therapy and occupational therapy evaluations as needed.5 | Dental care twice a year in HPP and every six months in XLH.5 7 Ongoing PT. | Maintenance program. |
| Behavioral health and nutrition | Screen for pain burden, function and mood; psychological and social work support as needed. No excess vitamin D in HPP.5 | Pain management; NSAIDs for bone pain and osteoarthritis in HPP.5 | As needed. |
| Community | HPP and XLH patient organizations; registry enrollment. | Trial referral where approved therapy does not fit. |
Visit one
The map above is the evidence. This is what to do with the patient in the room. Each line comes from the Year 1 column and carries the same citations.
| Ask | Fractures, especially metatarsal and thigh, and how they healed; chronic musculoskeletal pain; early atraumatic loss of teeth; pseudogout or chondrocalcinosis; known nephrocalcinosis.1 Current or past bisphosphonate, denosumab, vitamin D or pyridoxine.1 5 Dental abscesses; family history of XLH or of low phosphate passed down an X-linked dominant line.2 |
| Examine | Height, gait, bony tenderness and range of motion, lower limb alignment, dentition.1 2 |
| Order | Every prior ALP. Repeat ALP with calcium, phosphate, PTH and 25-hydroxyvitamin D, and the tests that exclude the acquired causes the history points to: TSH, magnesium, zinc, celiac serology among them. Plasma PLP after a week off pyridoxine. ALPL sequencing.1 If phosphate is low: fasting phosphorus with TmP/GFR and a hypophosphatemia gene panel that includes PHEX.2 |
| Refer | Endocrinology or metabolic bone with the ALP history, the PLP level and the gene result; dentistry.5 Where: the esoteric assays, clinical expertise and specialist rosters. |
| Tell the patient | That a persistently low ALP can be a genetic bone disorder and is worth confirming before any osteoporosis drug; why the bisphosphonate is on hold; that a positive result matters for relatives. |
| Document | Every ALP value with its date, the acquired causes excluded, the major and minor criteria met, current bone-active drugs, and the referral question. |
Roster for this cohort
Drawn from the esoteric assays roster (PLP, ALPL and hypophosphatemia gene panels, FGF23), the clinical expertise roster (metabolic bone and biochemical genetics consults), the advanced imaging roster (skeletal survey and imaging of pseudofractures), the specialist roster (endocrinology, rheumatology, nephrology), the empiric therapies roster (specialty pharmacy for asfotase alfa and burosumab), and the therapists roster. The roster is forming; members propose and vet entries in the cohort's Slack channel.
Readings
- GeneReviews: Hypophosphatasia, X-Linked Hypophosphatemia. University of Washington.
- Khan AA, Brandi ML, Rush ET, et al. Hypophosphatasia diagnosis: current state of the art and proposed diagnostic criteria for children and adults. Osteoporos Int. 2024. Table 1 (causes of low ALP) and Table 4 (the criteria) are the two tables to keep at hand.
- Khan AA, Ali DS, Appelman-Dijkstra NM, et al. X-linked hypophosphatemia management in adults: an International Working Group clinical practice guideline. J Clin Endocrinol Metab. 2025.
References
- Khan AA, Brandi ML, Rush ET, et al. Hypophosphatasia diagnosis: current state of the art and proposed diagnostic criteria for children and adults. Osteoporos Int. 2024;35(3):431-438. doi:10.1007/s00198-023-06844-1
- Khan AA, Ali DS, Appelman-Dijkstra NM, et al. X-linked hypophosphatemia management in adults: an International Working Group clinical practice guideline. J Clin Endocrinol Metab. 2025;110(8):2353-2370. doi:10.1210/clinem/dgaf170
- Schäfer VS, Hinman J, Moss K, et al. Prevalence of hypophosphatasia in general and selected patient populations: a systematic review. Osteoporos Int. 2026. doi:10.1007/s00198-026-08227-8
- Sutton RA, Mumm S, Coburn SP, et al. "Atypical femoral fractures" during bisphosphonate exposure in adult hypophosphatasia. J Bone Miner Res. 2012;27(5):987-994. doi:10.1002/jbmr.1565
- Dahir KM, Nunes ME. Hypophosphatasia. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2026. NBK1150
- Bhattacharyya T, Jha S, Wang H, et al. Hypophosphatasia and the risk of atypical femur fractures: a case-control study. BMC Musculoskelet Disord. 2016;17:332. doi:10.1186/s12891-016-1191-8
- Laurent MR, Harvengt P, Mortier GR, Böckenhauer D. X-linked hypophosphatemia. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2026. NBK83985
- Kishnani PS, Rockman-Greenberg C, Rauch F, et al. Five-year efficacy and safety of asfotase alfa therapy for adults and adolescents with hypophosphatasia. Bone. 2019;121:149-162. doi:10.1016/j.bone.2018.12.011
- Insogna KL, Briot K, Imel EA, et al. A randomized, double-blind, placebo-controlled, phase 3 trial evaluating the efficacy of burosumab, an anti-FGF23 antibody, in adults with X-linked hypophosphatemia: week 24 primary analysis. J Bone Miner Res. 2018;33(8):1383-1393. doi:10.1002/jbmr.3475
References retrieved from PubMed on 2026-10-30. Care maps are peer-authored clinical frameworks for network members, not individualized medical advice, and are reviewed at each yearly cycle.