Hypophosphatasia (HPP) is a rare genetic disease that affects the development of bones and teeth in children.[1] Research in recent years suggests that low levels of an enzyme called alkaline phosphatase (ALP) can cause bone loss and stress fractures in adults. Keep reading to learn what you may want to talk with your doctor about.
What we know
HPP is caused by the absence or reduced amount of an enzyme called tissue-nonspecific alkaline phosphatase (TNSAP), also called bone-specific alkaline phosphatase (BSAP). The absence of BSAP raises the level of inorganic pyrophosphate (Pi), which prevents calcium and phosphate from creating strong, mineralized bone. Without BSAP, bones can become weak. In its severe form, HPP is fatal. This happens in 1-in-100,000 births.
Because HPP is genetic, it can appear in adults as well. A recent study identified a milder, more common form of HPP that occurs in 4-in-1,000 adults.[2] This form of HPP is usually seen in early middle-aged adults who have low bone density and sometimes have stress fractures in the feet or thigh bones. Sometimes, these patients lost their baby teeth early, but not always.
HPP is diagnosed by measuring blood levels of TNSAP and vitamin B6. An elevated vitamin B6 level [serum pyridoxal 5-phosphate (PLP)][3] in a patient with a TAP level ≤40 or in the low end of normal can be diagnosed with HPP. Almost half of the adult patients with HPP in the large study had TAP >40, but in the lower end of the normal range.[4]
How Hypophosphatasia and Osteoporosis Are Connected
Some people who have stress fractures get a bone density test and if the results are low, they are treated with an osteoporosis medicine. The first-line osteoporosis medicines are bisphosphonates such as Fosamax® (alendronate sodium), Actonel® (risedronate sodium), Boniva® (ibandronic acid), and Reclast® (zoledronic acid) These medicines work by slowing the breakdown of bone. In most patients, they effectively reduce the risk of fractures. However, because bisphosphonates are analogs (mimics) of Pi, which is elevated in HPP, patients with HPP should not be treated with bisphosphonates.
The Connection Between HPP and Atypical Femur Fractures
Atypical femur fractures (AFFs) have been associated with long-term use of bisphosphonates since they were first observed in 2007.[5] AFFs are rare, compared to how effectively bisphosphonates prevent hip fractures and vertebral fractures. Nonetheless, patients have become frightened about the risk of AFF. Because of this fear, there has been a substantial decline in the use of bisphosphonates. In turn, we are now seeing an increase in the rate of hip fractures in the U.S. In a meta-analysis of almost 100,000 patient-years of randomized control trial experience with alendronate sodium, risedronate sodium, ibandronate sodium and ibandronic acid and zoledronic acid requested by FDA, there was no signal for AFFs in the treated group vs the placebo group.[6]
There is now a possible explanation for AFFs. They could be happening in patients who have undiagnosed HPP and received the wrong fracture prevention medicine.
What You Can Do
Before deciding on a medicine for osteoporosis, talk with your health care provider about the best choice available. This choice will depend on the health of your skeleton.
- Ask your health care provider to review your total alkaline phosphatase (TAP) and obtain a vitamin B6 level [serum pyridoxal 5-phosphate (PLP)] if your TAP is in the lower end of the normal range (40-60) or is below 40, to rule out HPP. If your B6 level is elevated, you may have HPP, and you would be a candidate for Strensiq®, Tymlos®or Forteo® — but not a bisphosphonate or Prolia® (denosumab).
- Ask your doctor about your bone turnover rate. Tests might include a CTx, NTx, BSAP or P1NP. If you have a low rate of bone formation (low BSAP or P1NP) and an elevated risk of fracture, you are a candidate for Tymlos®or Forteo® — but not for a bisphosphonate or Prolia® (denosumab).
- After your bone density test, calculate your fracture risk using either the American Bone Health Fracture Risk Calculator™ or the FRAX® fracture risk assessment tool. If you have low bone density but are at low fracture risk, you are not a candidate for an osteoporosis medicine. You do need to make sure to take preventive steps to reduce further bone loss.
There is a medicine approved to treat HPP called Strensiq® (asfotase alfa). Patients who are not candidates for that medicine may be prescribed either Tymlos® (abaloparatide) or Forteo® (teriparatide) for their osteoporosis.
View the Encyclopedia of Rare Bone Diseases
References:
[1] Whyte MP, Mahuren JD, Vrabel LA, Coburn SP. Markedly increased circulating pyridoxal-5′-phosphate levels in hypophosphatasia. Alkaline phosphatase acts in vitamin B6 metabolism. J Clin Invest. 1985 Aug;76(2):752-6. doi: 10.1172/JCI112031. PMID: 4031070; PMCID: PMC423894.
[2] Dahir KM, Tilden DR, Warner JL, Bastarache L, Smith DK, Gifford A, Ramirez AH, Simmons JS, Black MM, Newman JH, Denny JC. Rare Variants in the Gene ALPL That Cause Hypophosphatasia Are Strongly Associated With Ovarian and Uterine Disorders. J Clin Endocrinol Metab. 2018 Jun 1;103(6):2234-2243. doi: 10.1210/jc.2017-02676. PMID: 29659871; PMCID: PMC6456921.
[3] Whyte, 1985.
[4] Dahir, 2018.
[5] Goh SK, Yang KY, Koh JSB, Wong MK, Chua SY, Chua DTC, Howe TS. Subtrochanteric insufficiency fractures in patients on alendronate therapy. J Bone Joint Surg [Br] 2007;89-B:349-53. Received 17 May 2006; Accepted after revision 8 November 2006
[6] U.S. Food and Drug Administration. FDA drug safety communication: Ongoing safety review of oral bisphosphonates and atypical subtrochanteric femur fractures. Available at: https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/fda-drug-safety-communication-ongoing-safety-review-oral-bisphosphonates-and-atypical. Accessed March 21, 2022.
Revised: March 21, 2022
