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Keywords:

  • ALENDRONATE;
  • ALKALINE PHOSPHATASE;
  • ANTIRESORPTIVES;
  • OSTEOMALACIA;
  • OSTEOPOROSIS;
  • PSEUDOFRACTURE;
  • PYRIDOXAL PHOSPHATE;
  • PYROPHOSPHATE;
  • STRESS FRACTURE;
  • VITAMIN B6;
  • ZOLENDRONATE

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Materials and Methods
  6. Results
  7. Discussion
  8. Disclosures
  9. Acknowledgements
  10. References

We report a 55-year-old woman who suffered atypical subtrochanteric femoral fractures (ASFFs) after 4 years of exposure to alendronate and then zolendronate given for “osteoporosis.” Before alendronate treatment, she had low bone mineral density. After several months of therapy, metatarsal stress fractures began. Bisphosphonate (BP) administration was stopped following the ASFFs, and the adult form of hypophosphatasia (HPP) was diagnosed from low serum alkaline phosphatase (ALP) activity, high endogenous levels of two natural substrates for the “tissue-nonspecific” isoenzyme of ALP (TNSALP), and a heterozygous mutation within the gene that encodes this enzyme. Experience with other HPP families showed that her mutation (Arg71His) with a second defective TNSALP allele can cause severe HPP in infancy, and when heterozygous can cause mild HPP featuring premature loss of deciduous teeth in children. Because the skeletal disease of HPP results from extracellular accumulation of the TNSALP substrate inorganic pyrophosphate (PPi) and its inhibitory effect on mineralization, perhaps HPP patients or carriers will have adverse effects from BPs. BPs are analogues of PPi and can suppress bone turnover but also deactivate TNSALP. Our report is the first of BP exposure preceding ASFFs in adult HPP. To explore a potential role for TNSALP deactivation in ASFFs, mutation analysis of TNSALP should be studied in a cohort of these patients. Meanwhile, clinicians must suspect HPP when clinical or laboratory clues include premature loss of primary dentition, pseudofractures or recurrent poorly healing metatarsal stress fractures, a family history suggestive of HPP, or low serum ALP activity. If HPP is documented, BP treatment might be avoided. To establish the diagnosis of HPP, assays for two natural substrates for TNSALP and TNSALP mutation analysis are available in commercial laboratories. With positive findings, radiological or bone biopsy evidence of acquired osteomalacia would indicate the adult form of this inborn-error-of-metabolism. © 2012 American Society for Bone and Mineral Research.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Materials and Methods
  6. Results
  7. Discussion
  8. Disclosures
  9. Acknowledgements
  10. References

Two monogenic disorders that cause osteomalacia, hypophosphatasia (HPP)1 and X-linked hypophosphatemia,2 can manifest femoral pseudofractures that are mimicked by the prodromal lesions for “atypical subtrochanteric femoral fractures” (ASFFs) associated with bisphosphonate (BP) therapy for osteoporosis (OP).3–5 Furthermore, ASFFs have been reported in additional heritable diseases of low bone turnover—osteopetrosis6, 7 and pycnodysostosis.8

HPP is the inborn-error-of-metabolism characterized biochemically by low serum alkaline phosphatase (ALP) activity (hypophosphatasemia) and caused by loss-of-function mutation(s) within the gene that encodes the “tissue-nonspecific” isoenzyme of ALP (TNSALP).9 Consequently, the natural substrates of this cell surface enzyme accumulate extracellularly9 and include: (1) phosphoethanolamine (PEA), a component of the phosphatidylinositol-glycan linkage apparatus that couples some proteins to cells; (2) pyridoxal 5′-phosphate (PLP), the major circulating form of vitamin B6; and (3) inorganic pyrophosphate (PPi), an inhibitor of mineralization and the ancestral molecule for the BPs.10 In HPP, the high extracellular level of PPi blocks hydroxyapatite crystal propagation and thereby causes rickets during growth or osteomalacia in adults.11

We describe a middle-aged woman who was given alendronate orally and then zolendronate intravenously for presumed OP. After 4 years of BP exposure, she suffered simultaneous ASFFs. The adult form of HPP was then documented. What portion of the “OP” population with ASFF harbors a TNSALP mutation requires investigation.

Case Report

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Materials and Methods
  6. Results
  7. Discussion
  8. Disclosures
  9. Acknowledgements
  10. References

A 55-year-old Caucasian woman had been healthy until age 49 years. She had no history of rickets or dental problems, and specifically no known premature loss of her primary dentition. Menopause was at age 45 years.

In July 2005, at 49 years of age, she tripped and had pain in the left shin and ankle (Fig. 1). Radiographs were negative, but a bone scan of the legs showed increased radionuclide uptake only in the anterior cortex of the distal tibia interpreted as “stress periostitis.”

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Figure 1. Timeline for the patient's clinical course and bisphosphonate therapy.

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In July 2006, bone mineral density (BMD) assessed by dual-energy X-ray absorptiometry (DXA) (GE Healthcare, Bucks, UK) showed a low T-score (or standard deviations [SDs] below young normal values) of −2.5 at the L2–4 spine and −2.0 at the total hip consistent with “OP.” Elsewhere, she was prescribed alendronate 70 mg orally (p.o.) weekly, calcium 1500 mg p.o. daily, and vitamin D3 500 units p.o. daily. She took the regimen inconsistently.

In October 2006, painful swelling developed in her right foot. Radiographs showed “extremely osteoporotic” bones. A second bone scan of the feet revealed an acute stress fracture in the right second metatarsal (Fig. 2AC). Whole-body images were also obtained and were otherwise unremarkable, including no evidence of femoral lesions (Fig. 2D,E).

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Figure 2. (AC) Different views on bone scintigraphy in November 2006 reveal intense increased uptake consistent with a fractured right second metatarsal. The additional moderate uptake in the right midfoot and hindfoot is much less focal and likely due to some altered mechanics/weight-bearing because of the fracture. (D, E) Whole-body images reveal no evidence of femoral pseudofractures in November 2006.

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In July 2007, she fell and sustained a right wrist fracture that required open reduction and internal fixation and an injury to the right ankle that became bruised and swollen. Radiographs showed a cortical avulsion from the head of the right talus bone.

In January 2008, pain occurred in the left foot where radiographs showed an old healed fracture of the distal second metatarsal.

In May 2008, she developed transient left mid-thigh “shooting” pains while standing or walking. No radiographs or bone scans were performed, and “bursitis” was diagnosed.

In July 2008, after 2 years of alendronate exposure, the same DXA instrument showed improvement in spine and total hip BMD, with T-scores of −2.2 and −1.7, respectively.

In October 2008, pain in the left foot returned. Radiographs were reported to show an old or healing stress fracture of the distal third metatarsal (Fig. 3), and a third bone scan of the legs also suggested a stress fracture at the base of the left third metatarsal. Increased uptake in the region of the navicular bones was attributed to either inflammatory arthropathy or, less likely, to spontaneous avascular necrosis of the navicular bones or further stress fractures.

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Figure 3. In October 2008, radiographs revealed healing of a left third metatarsal stress fracture (arrow).

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In January 2009, at a different OP clinic, DXA (Hologic, Waltham, MA, USA) showed L1–4 spine and total hip T-scores of −2.4 and −1.6, respectively. Alendronate was changed to intravenous zolendronate, and she was administered her first dose (5 mg) in February 2009, while she continued the calcium supplement and was given more vitamin D3 (1000 units) daily. Investigation for secondary causes of OP documented a normal serum level of calcium at 2.31 mmol/L (2.10–2.55 Nl) as well as creatinine, parathyroid hormone (PTH), and 25-hydroxyvitamin D at 59 nmol/L (25–135 Nl; <39 = “insufficiency”). However, there was hypophosphatasemia with serum ALP of <25 and 26 U/L on separate occasions (42–116 Nl), and hyperphosphatemia with serum inorganic phosphate (Pi) concentration of 1.48 mmol/L (0.80–1.40 Nl).

In July 2009, her right thigh “gave way while walking.” Ultrasonography was negative. Many months of painful limp followed, and while walking, turning, or twisting she had an occasional sensation that either the right or left thigh might further give way. Bilateral thigh pain was greater on the left. At rest, no pain occurred in the thighs or groins.

In August 2009, left lateral foot pain resumed. Radiographs showed a bony process arising from the anterosuperior aspect of the calcaneus, and some evidence of a healing stress fracture of the right second metatarsal.

In February 2010, a fourth DXA study (Hologic) revealed an identical spine BMD compared to January 2009. The hip was not studied. A second infusion of 5 mg zolendronate was given.

In June 2010, after 4 years of BP exposure, while standing at work and slightly rotating her trunk, our patient collapsed to the floor with bilateral subtrochanteric femoral fractures (Fig. 4A). It seemed that at least one of the fractures preceded the fall. She also refractured her right wrist. The bilateral femur fractures were fixed with compression screws and plates.

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Figure 4. (A) Bilateral acute subtrochanteric femoral fractures occurred in June 2010 after approximately 4 years of BP exposure. Note also the cortical thickening of both upper femoral shafts. (B) In August 2011, approximately 18 months after cessation of BP exposure, there was persisting thigh pain but evidence of fracture healing with callus formation although the cortical fracture lines can still be seen bilaterally. BP = bisphosphonate.

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In February 2011, she declined a third zolendronate infusion.

In March 2011, when first assessed by us (R.A.L.S.), she was walking well and had returned to work. Her orthopedist reported the fractures were healing appropriately. In view of her medical history and laboratory findings, the diagnosis of HPP was considered. She came from the Province of Saskatchewan, but denied any genetic connection with the Mennonite population in Manitoba, Canada (the neighboring Province to Saskatchewan) in whom carriers of HPP are common (1/25 individuals) due to a founder mutation of TNSALP.12 In support of HPP, urinary phosphoethanolamine (PEA) (Provincial Health Services Authority Laboratories, BC Children's and Women's Health Centre of BC, Vancouver, BC, Canada) was elevated at 165 µmol/gm creatinine (upper reference limit ∼70).

In August 2011, she had severe weight-bearing pain in the left thigh and milder pain in the right thigh of several weeks. Radiographs showed apparently stable femoral fractures which another orthopedist considered clinically and radiographically united (Fig. 4B). The cause of the weight-bearing pain was not clear. If evidence of fracture instability developed, consideration would be given to intramedullary fixation,13 or to a trial of teriparatide (PTH fragment 1–34) therapy14, 15 (see Discussion).

In November 2011, a plate-fixation screw was noted to be broken on a radiograph of the left hip. An intramedullary rod is being proposed. Serum ALP, more than 1 year after her last dose of zolendronate, remained low at 31 and 38 U/L (42–116 Nl). Chart review revealed that her only serum ALP determination before BP exposure was in 2004, and was 40 U/L (40–120 Nl). The only serum Pi measurement was the elevated value in keeping with HPP of 1.48 mmol/L in 2006 (soon after alendronate exposure began). Accordingly, we studied our patient further for adult HPP.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Materials and Methods
  6. Results
  7. Discussion
  8. Disclosures
  9. Acknowledgements
  10. References

Following informed written consent, a nonfasting blood sample was collected in August 2011. Serum was assayed at Shriners Hospital for Children; St. Louis, MO, USA for ALP and bone-specific ALP using the MicroVue BAP EIA kit (Quidel Corp., San Diego, CA, USA). Plasma PLP was measured in this patient, and had been assayed in most of our previous HPP patients, in our research laboratory in Fort Wayne, IN, USA.16

Genomic DNA was extracted from peripheral blood leukocytes using the Gentra Puregene DNA extraction kit (Invitrogen, Carlsbad, CA, USA). TNSALP mutation analysis was performed in our research laboratory by sequencing all of the coding exons and adjacent mRNA splice sites of this gene using previously described PCR and sequencing primers and conditions.17

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Materials and Methods
  6. Results
  7. Discussion
  8. Disclosures
  9. Acknowledgements
  10. References

Our patient's serum ALP activity was low at 41 U/L (50–136 Nl), Pi concentration unremarkable at 4.0 mg/dL (2.5–4.9 Nl), and bone-specific ALP activity low-normal at 12 U/L (10–30 Nl). Plasma PLP level was distinctly elevated at 346 nM (7–107 Nl) off multivitamins. TNSALP mutation analysis revealed one heterozygous mutation: c.212G > A, p.Arg71His in exon 4.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Materials and Methods
  6. Results
  7. Discussion
  8. Disclosures
  9. Acknowledgements
  10. References

Our patient received sequentially two amino-BPs for a presumed diagnosis of postmenopausal OP based primarily on her DXA T-score of –2.5 in the lumbar spine. Although this T-score perhaps reflected osteomalacia developing in adult HPP,18 recurrent metatarsal stress fractures, the classic presentation for adult HPP,1, 9 began after BP administration started. Subsequently, hypophosphatasemia, hyperphosphatemia, elevations of two natural substrates for TNSALP (PEA and PLP), and additional fractures including ASFFs were typical of adult HPP.1, 9, 13 Indeed, she seemed like an asymptomatic HPP “carrier” until soon after her first BP exposure.9 She had no history of rickets in childhood that is sometimes reported by adults with HPP,19 and no member of her family (albeit small with two of three sisters living, one daughter, one granddaughter) had this diagnosis. Furthermore, she did not report premature loss of her deciduous teeth (ie, before age 5 years), which is present in nearly all (∼98%) pediatric patients with HPP.20 Additionally, before BP exposure, serum ALP (40 U/L) was reported at the lower limit of the normal range (40–120 Nl). Her father and daughter have distinctly low serum ALP activity, but are said not to have clinical manifestations of HPP.

Our patient's thigh pain for approximately 1 year before her ASFFs was probably explained by femoral pseudofractures, which eventually fractured completely.13, 21 We were unable to find in the preceding bone scans or DXA studies any evidence of a cortical defect in the femoral regions imaged, but the most recent whole-body scan and hip DXA assessments were 3.5 years and 18 months prior to the ASFFs, respectively, and before she first received zolendronate.

Femoral pseudofractures (typically bilateral, painful, and in the lateral subtrochanteric diaphysis) are a hallmark of adult HPP.21 These are not “stress fractures” that heal with rest (eg, non-weight bearing), but pseudofractures (Looser's zones, Milkman fractures) indicative of underlying osteomalacia.22 In adult HPP, these femoral pseudofractures mend spontaneously only if they first go on to complete transverse fractures. They will heal if they instead receive prophylactic or acute treatment with intramedullary fixation.13 In this way, the femoral lesions that precede ASFFs during BP therapy in OP seem similar.3

It is now recognized that relatively long-term BP treatment for OP is associated with ASFFs.3–5 The incidence increases with the duration of BP therapy; eg, from 2 to 78 yearly per 100,000 cases for 2 versus 8 years of BP exposure, respectively.23 In another review, the median duration of BP treatment prior to the ASFF was 7 years.4

Because BPs are analogs of PPi, we have speculated that HPP patients may be sensitized to the effects of BPs, including acquired “ASFFs.”3 Of interest, toxicity from the first-generation BP, etidronate, mimics HPP by causing rickets or osteomalacia, myopathy, and hyperphosphatemia.24 Additionally, the amino-BPs, including alendronate and zolendronate, can inhibit TNSALP by binding both Zn++ and Mg++.25 Perhaps patients diagnosed with OP but carrying a TNSALP mutation are prone to develop ASFFs from BPs. Our patient is the first example to support this concern. She has a single deactivated TNSALP allele with just a 4-year exposure to BPs before she suffered fractures that fit all five major features of ASFF3: subtrochanteric location, transverse or short oblique orientation, minimal or no trauma, a medial spike when the fracture becomes complete, and absence of comminution. Our patient also exhibited several minor features of ASFF,3 including a generalized increase in the cortical thickness of the femoral diaphysis,26 bilaterality, prodromal pain, and delayed healing.

Now, 250 different mutations within TNSALP (76% missense) and eight TNSALP coding region polymorphisms (five synonymous and three nonsynonymous) have been identified in HPP patients (http://www.sesep.uvsq.fr/03_hypo_mutations.php#presentation).27 In our experience with more than 200 HPP patients, all have had at least one defective TNSALP allele.

Adult HPP can result from the presence of autosomal dominant (AD) or autosomal recessive (AR) TNSALP mutation(s).9 Although not detailed in the medical literature, adult carriers of HPP may or may not manifest hypophosphatasemia or elevated blood or urine levels of the TNSALP substrates PEA, PLP, or PPi.12 Who among them will develop overt HPP (and why) is not clear. Studies of siblings with HPP show that unknown factors can significantly condition the variable expressivity of this metabolic bone disease.9

To our knowledge, our patient is the first to harbor a single mutated TNSALP allele and manifest bilateral ASFFs after BP exposure. She had a relatively short course of BPs (4 years), but using increasingly potent preparations. Although we cannot exclude that her HPP was just beginning to present clinically then, and would alone have led to her ASFFs, her relatively brief BP exposure before symptoms of bilateral femoral pseudofractures is consistent with acceleration by BPs.

We found that our patient carried one TNSALP missense mutation, c.212G > A, p.Arg71His. This defect was reported in 2001 to be the maternal allele in a compound heterozygous neonate with lethal HPP (using a different nomenclature called Arg54His or R54H).28 However, clinical information was not available concerning the mother.28 In 2003, we reported that an 8-month-old girl with infantile HPP, who seemed to benefit from marrow cell transplantation,29 was a compound heterozygote for Arg71His on the paternal allele. This 31-year-old father was hypophosphatasemic with an elevated plasma PLP level, but normophosphatemic. We do not know if he had dento-osseous disease. Some of our other HPP patients carry only this c.212G > A, p.Arg71His mutation. The mother of one, a boy with odonto-HPP, also carries this Arg71His mutation and is hypophosphatasemic, normophosphatemic, and has elevated plasma PLP levels both before and especially after pyridoxine loading. We have used pyridoxine loading to study patients and carriers with HPP.12 Patients with HPP have elevated plasma PLP levels that become especially high after an oral challenge with pyridoxine hydrochloride—reflecting increased production yet diminished hydrolysis of PLP by cell surface TNSALP.12 This mother, at age 40 years, had normal BMD of the spine and hip assessed by DXA. Also, his maternal grandmother repeatedly had borderline or slightly low serum ALP activity assayed elsewhere, but no history of fractures. Thus, our current patient harbors a TNSALP defect that can cause odonto-HPP in childhood, or can be found in adult “carriers” of HPP. The Arg71 mutation causes severe HPP (perinatal or infantile HPP) when combined with another defective TNSALP allele, or clinically mild odonto-HPP in childhood when it occurs as a single, heterozygous mutation. Thus, perhaps it manifests dominant-negative effects. Nevertheless, we know of no one, other than our patient, heterozygous for Arg71His who has femoral fractures or adult HPP. However, the long-term outcome for heterozygosity for Arg71His remains unknown.

In some individuals, Arg71 is mutated to an amino acid other than His, including Arg71Cys, Arg71Ser, and Arg71Pro. In 1992,30 we documented two lethal HPP patients (3 hours, and 6 months after birth) in whom Arg71Cys was accompanied by a second different TNSALP mutation (either Gln207Pro or Asp294Ala, respectively). When expressed in vitro, Arg71Cys TNSALP (formerly Arg54Cys) had just 1.1% of wild type TNSALP activity.31 In 2001, Orimo and colleagues31 reported severe HPP where only Arg71Ser was identified, but a second TNSALP mutation was probably not detected due to technical limitations of the single-strand conformational polymorphism analysis.31 In fact, we have found that three different TNSALP Arg71 defects (Arg71Cys, Arg71Ser, and Arg71Pro) can cause mild HPP when heterozygous. We care for three unrelated families (unpublished data) in whom the proband has odonto-HPP and has TNSALP Arg71Cys, Arg71Ser, or Arg71Pro, and each of the young parents harboring the mutation is hypophosphatasemic but normophosphatemic, with normal BMD on DXA of the lumbar spine and total hip. Additionally, we found the plasma PLP levels pre- and post-vitamin B6 loading were elevated for Arg71Cys and Arg71Ser, but normal for Arg71Pro. However, no information is, as yet, available for any of their carrier grandparents to understand the outcome. Overall, we find that the DNA sequence that encodes Arg71 of TNSALP seems to be a “hot spot” for missense mutation. Early in life, these Arg71 mutations can cause odonto-HPP when inherited alone, or severe HPP when combined with a second defective TNSALP allele.

In 1957, the prevalence of severe HPP was estimated to be 1/100,000 in Canada.32 Therefore, the AR carrier prevalence there would be ∼1/160. For the special circumstance of the Canadian Mennonite population,12 owing to a founder mutation (p.Gly334Asp) where severe HPP occurs in approximately 1/2500 births, ∼1/25 individuals is a “carrier”. In France, in 2011, Mornet and colleagues33 estimated from DNA specimens referred to their laboratory for TNSALP mutation analysis that the prevalence of severe HPP is ∼1/300,000. They then calculated that moderate, dominant forms of HPP would have a prevalence of about 1/6370, and a population frequency of ∼1/2036 for heterozygotes carrying a severe dominant mutated TNSALP allele.

If in North America the prevalence of a carrier of a potentially significant AD TNSALP defect is 1/2036,33 a higher prevalence in patients with ASFFs and especially in BP-treated “OP” patients with ASFFs would implicate HPP and BPs in ASFFs. Perhaps, such TNSALP mutations will be more prevalent among patients sustaining ASFFs after relatively short periods of BP exposure than the reported median of seven years.3, 4 In 2012, rare coding variants in TNSALP were associated by Nielson and colleagues34 with low serum ALP activity, higher blood phosphate levels, and low BMD. The authors concluded “it is intriguing to consider the possibility that a mild genetic form of HPP… might explain some proportion of adult-onset OP.”

Our findings indicate that TNSALP mutation analysis of a cohort of patients with ASFFs should be undertaken to understand the prevalence of these mutations, including those with “OP” and ASFFs, and any impact of BP treatment.

BMD can be subnormal in HPP, so that especially adult HPP patients may be erroneously diagnosed with “OP.” However, age-appropriate reference ranges for serum ALP activity are now routinely available and should make low values obvious during biochemical profiling.9 In this situation, the multiple causes of hypophosphatasemia should be considered (Table 1). Fortunately, to diagnose HPP, assays for plasma PLP levels are now readily available (see the final paragraph below) and relatively inexpensive. Unless there is ingestion of excessive amounts of vitamin B6, plasma PLP levels are not expected to be elevated in circumstances other than HPP.9 In fact, PLP levels can be low in other forms of rickets or osteomalacia when serum ALP levels are characteristically elevated and hydrolyze PLP.35 However, it is not practicable to screen all patients starting BP treatment by measuring plasma PLP, or serum or urine PEA or PPi (a research procedure).36 Likewise, TNSALP mutation analysis or radiological procedures or bone biopsy to screen for osteomalacia18 are not feasible. Accordingly, unless the features of HPP are recognized, it seems that some adults with HPP will go undiagnosed before receiving BPs for “OP.” In fact, a patient15 later diagnosed with HPP presented with painful femoral pseudofractures and a low femoral BMD attributed to OP and was prescribed risedronate. Subsequently, her pain and fractures worsened, and the risedronate was stopped after 2.5 years and intramedullary rods were placed bilaterally. After a further 10 months, the fracture healing was incomplete and the pain remained severe. By this time, the diagnosis of HPP had been made and treatment was started with teriparatide. In some adults with HPP, “off label” use of teriparatide has been reported to provide pain relief and to promote healing of femoral pseudofractures.14, 15 Within several months, striking pain relief accompanied radiological fracture healing in this patient.15 Unfortunately, TNSALP mutational analysis was not reported. However, in a recent preliminary communication of an uncontrolled observational study of BP-treated OP patients with ASFFs,37 it was unclear whether teriparatide helped. Instead, for at least the past 25 years, the subtrochanteric femoral pseudofractures of adult HPP have typically been treated with a load-sharing intramedullary fixation device, rather than with load-sparing plating.13 There is no established medical treatment for HPP, but reports of enzyme replacement using bone-targeted TNSALP in severe pediatric forms of HPP are encouraging.38

Table 1. Causes of Low Serum ALP Activity
  1. ALP = alkaline phosphatase; EDTA = ethylene diamine tetraacetic acid.

Cardiac bypass surgeryMilk-Alkali syndrome
Celiac diseaseMultiple myeloma
Clofibrate therapyOsteogenesis imperfecta, type II
Cleidocranial dysplasiaPernicious or profound anemia
Cushing's syndromeRadioactive heavy metals
HypophosphatasiaStarvation
HypothyroidismVitamin C deficiency
Improperly collected blood (oxalate, EDTA)Vitamin D intoxication
Inappropriate reference rangeWilson's disease
Massive transfusionZn++ or Mg++ deficiency

Until more is known, clinicians should identify, among patients for whom BPs are being considered, those who might represent, or later manifest, HPP. Clues include a history of premature loss of primary dentition, dentures early in adult life, recurrent poorly-healing metatarsal stress fractures, a family history of rickets or osteomalacia, bone pain or tenderness and radiographic findings suggestive of osteomalacia (especially lateral cortical fractures in the proximal femur), as well as low and perhaps low-normal serum ALP activity.9 HPP could then be substantiated by a high serum or urinary PEA level or by an elevated plasma PLP level disclosed either by a PLP or “vitamin B6” assay, for example from Laboratory Corporation of America (Burlington, NC, USA), Mayo Medical Laboratories (Rochester, MN, USA), or Quest Diagnostics (San Juan Capistrano, CA, USA). Now, if needed, TNSALP mutation analysis is commercially available to detect the genetic basis for this inborn-error-of-metabolism. Using this information, the astute clinician should be able to diagnose HPP, and might avoid the use of BPs. The contribution of TNSALP mutations to BP-related ASFFs requires investigation.

Disclosures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Materials and Methods
  6. Results
  7. Discussion
  8. Disclosures
  9. Acknowledgements
  10. References

MPW consults for and has research grant support from Enobia Pharma, Montreal, Canada, and has stock in Merck, Inc., Boston, MA, USA.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Materials and Methods
  6. Results
  7. Discussion
  8. Disclosures
  9. Acknowledgements
  10. References

This work was supported in part by Shriners Hospitals for Children, The Clark and Mildred Cox Inherited Metabolic Bone Disease Research Fund, The Hypophosphatasia Research Fund, and The Barnes-Jewish Hospital Foundation. We thank Dr. Helen Eng (White Rock, British Columbia, Canada) for referring the patient and providing medical records. Margaret Huskey performed the TNSALP sequence analysis. We are grateful to Dr. Jennifer Demertzis, Musculoskeletal Section, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO for helping to illustrate the radiological findings.

Authors' roles: All authors helped to write the manuscript. RALS diagnosed and recognized the potential importance of the coexisting HPP and bisphosphonates with ASFFs, organized clinical studies, assembled the information from multiple sources for the case history, and wrote the first draft of the manuscript. SM performed TNSALP gene analysis and reviewed the mutation literature. SPC and KLE performed the plasma PLP analyses. MPW helped to synthesize the clinical, biochemical, radiological, and genetic studies.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Materials and Methods
  6. Results
  7. Discussion
  8. Disclosures
  9. Acknowledgements
  10. References
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