Introduction: HPP is caused by a missense mutation in the ALPL gene, which is inherited in either an autosomal recessive or dominant pattern, and results in loss or decreased activity of the TNSALP (Tissue Non-Specific Alkaline Phosphatase) enzyme1. It is rare, with a prevalence of 1 in 100000 births2, often resulting in a diagnostic delay.
Case presentation: A 30-year-old lady was referred to the Endocrine department by clinical genetics after being sent for DNA analysis following lethal skeletal dysplasia in two pregnancies. This confirmed carrier ALPL mutation status c.931G>A.
She had a mild phenotype hypophosphatasia with known dental enamel hypoplasia. Her husband also had an ALPL gene mutation (c 650 T > C variant).
She had a previous history of a wrist fracture as a child (fall from standing height) and shin pains with running but no fractures. She also has a history of knee pain with effusion, in keeping with a patellofemoral syndrome rather than hypophosphatasia. She had one serving of dairy daily and enjoyed walking. She never required steroids and had regular menstrual cycles since menarche at 14.
Medications included Vitamin D 1000 units daily and a pregnancy multivitamin.
Her family history includes osteoporosis in her mother at age 28 who sustained a coccygeal fracture during pregnancy and was treated with zoledronic acid infusions annually though was later found to carry the same ALPL mutation. Her grandfather had osteoporosis aged 40-50. Her grandmother had dental issues at the age of 20 requiring full dentures.
On examination, there were no clinical manifestations besides dental enamel hypoplasia.
On presentation in 2019 she had low alkaline phosphatase at 25 IU/ L (30-100 RR) with a repeat level of 30 IU/L in 2020. She had an elevated pyridoxal-5, -phosphate (PLP) in 2019 of 145 nmol/L (35-110). PLP is a substrate of ALP and due to the ALP mutation, the substrate accumulates. Another substrate, phosphoethanolamine is excreted in the urine, however, her levels were normal. In keeping with the low bone turnover state her CTx1 was low at 101 ng/ L (150-800) but her DPD and DPX cross-links were normal. Vitamin D level was normal. Her Bone Mineral Density (BMD) in mid 2020 demonstrated a femoral neck T score of -1.8 SD, Z score of -1.8 SD and a lumbar spine T score of 0.1 SD, Z-score - 0.2 SD.
She was advised to do weight-bearing exercises and incorporate 3 servings of dairy into her diet. There were no additional recommendations for pregnancy planning. She was advised that if she does experience a fracture or reduction in BMD she should avoid bisphosphonates as this can increase the fracture risk and that teriparatide could be considered outside of pregnancy. She was recommended for review in 12 months with BMD.
She subsequently had a natural pregnancy with no evidence of skeletal dysplasia and was reviewed six months post-partum at which point she was breastfeeding. There was no further fracture history though she did have chronic lower back pain post-delivery. ALP was at the lower end of normal at 43 U/L with a vitamin D of 72 nmol/ L. She had evidence of worsening BMD in December 2022 with a Z-score of -2.8 in her total right femur (T-score of -2.4). Lumbar spine Z score was -0.5 with a T score of -0.5.
She was recommended to cease breastfeeding immediately and for review in 9 months with repeat BMD and if worsening, to consider teriparatide. She has since had a CT pelvis to investigate the longstanding coccygeal pain post-delivery, which suggests an undisplaced cortical fracture of the first coccygeal segment. This now poses the dilemma of how best to manage her osteoporosis.
Literature:
There is conflicting evidence on the effect of lactation on BMD, with multiple cross-sectional and cohort studies suggesting a negative association between duration lactation and BMD3. Additional studies suggest a positive or no association between lactation and BMD3 and hence the management of osteoporosis in breastfeeding women with HPP is unclear.
As the skeletal disease of HPP results from the extracellular accumulation of the TNSALP substrate inorganic pyrophosphate (PPi) and its inhibitory effect on mineralization, HPP patients or carriers have adverse effects from bisphosphonates.4 Bisphosphonates are analogues of PPi and can suppress bone turnover but also deactivate TNSALP.4
Currently, evidence is limited to several case reports which demonstrate atypical femoral fractures during bisphosphonate exposure in adults with hypophosphatasia4.
Evidence for teriparatide is limited. Treatment with teriparatide to increase osteoblast production of ALP has been reported to date in a total of 10 adult patients. However, its effects on BMD have been variable5. Teriparatide reportedly improved pain, mobility, and fracture repair in two sisters with HPP ages 56 and 64 years and can be considered as a treatment option6.
There is a single case report of romosozumab use in an 81-year-old with hypophosphatasia and osteoporosis. Though ALP remained the same, after 1 year of Romosuzumab therapy, BMD improved by 21%, and 10% at the lumbar spine and total hip, respectively, suggesting benefit7.
There is promising evidence for asfotase alfa, an enzyme replacement therapy developed to treat HPP. A multi-centre randomised open-label study evaluating the efficacy and safety of asfotase alfa in patients aged 13-66 years with HPP demonstrated improvement in both PLP and PPi within subjects after 6 months and over 5 years of treatment with asfotase alfa (P <0.05). There was also improvement in gross motor function, muscle strength and reported functional disability over 5 years of treatment however no improvement in mean BMD. 8
Take-home:
1/ If you note a low ALP and features of osteoporosis, consider HPP.
2/ Bisphosphonates are associated with an increased risk of atypical femoral fractures in HPP.
3/ There is conflicting data to suggest lactation increases bone turnover.
4/ There is limited evidence for teriparatide, romosozumab and asfotase alfa in the management of osteoporosis in HPP.