Multiple Fractures, Low ALP and High B6 in an Elderly Patient

By Abby Abelson, MD, and Chad Deal, MD

Case

A 69-year-old female presented to our Center for Osteoporosis and Metabolic Bone Disease with a recent history of multiple fractures and a family history of premature tooth loss. Her father was reported to have only one tooth left at time of death. Although the patient reported no premature tooth loss, her daughter lost six teeth before age three. The patient’s first fracture was a wrist at age 53, then an ankle at 54 and fibula at 55. At age 66, she fractured her right femur and then her left femur the following year, requiring bilateral medullary rods. A DXA scan showed a lumbar spine T-score of -0.9 and hip T-score of -2.4.

Bilateral femur fractures with rods. The knees show chondrocalcinosis.

She was treated with alendronate sodium for four years in her 50s, teriparatide for two years and then several doses of denosumab. A chart review revealed that her alkaline phosphatase (ALP) levels had been consistently less than 40 IU/L. A vitamin B6 was ordered and was 283 (normal < 125 nm/L). X-rays of the knees were ordered and showed chondrocalcinosis. Genetic sequencing of the ALP gene revealed a pathologic variant associated with previous cases of hypophosphatasia (HPP).The patient was started on asfotase alfa in November of 2018.

The case illustrates late but severe disease manifestations of HPP. Treatment with antiresorptive agents was of no benefit and likely harmful. Patients with apparent osteoporosis and an ALP that is persistently below 40 IU/L should not be placed on an antiresorptive agent until the diagnosis of HPP is considered.

Disease prevalence

HPP is a rare metabolic bone disease, with an estimated prevalence of between 0.3 and 1/100,000 in severe forms, and more recent reports suggesting that moderate forms are substantially more frequent.

At Cleveland Clinic a review of medical records found over 600 patients with at least two ALP < 30 with no value ever above 40. Clinical review of these patients is ongoing.

A retrospective review over 10 years of 885,165 patients at Marshfield Clinic found persistent hypophosphatasemia in 1 of 1544 adult patients. Many of these patients were found to harbor previously unrecognized HPP. These adult patients had more crystalline arthritis, orthopedic surgery, chondrocalcinosis, calcific periarthritis, enthesopathy and diffuse idiopathic skeletal hyperostosis than a general adult patient population.

Disease etiology

In this inherited disease, mutations of the ALPL gene result in the reduction of tissue-non-specific isoenzyme of alkaline phosphatase (TNSALP) activity.

TNSALP is a cell-surface homodimeric phosphohydrolase that is richly expressed in the liver, kidney, skeleton and developing teeth. TNSALP substrates, including inorganic pyrophosphate (PPi) and pyridoxal 5-phosphate (PLP) (vitamin B6), accumulate extracellularly in HPP. PPi is a potent inhibitor of mineralization, and its excess in HPP explains many of the hard tissue complications of HPP, including premature loss of deciduous teeth, rickets in children, osteomalacia in adults, chondrocalcinosis, frequent fractures and calcific arthropathies. PLP, the major co-factor form of vitamin B6, explains the pyridoxine-dependent seizures of severe HPP. In adults, elevated PLP does not result in clinical symptoms but is a biomarker for the disease, in addition to low ALP.

How your patient may present

Rheumatologists most commonly see the adult form of HPP, one of six major forms of the disease. The adult form is characterized by muscle pain, muscle weakness, recurring stress fractures, osteomalacia, a history of dental abnormalities and calcium pyrophosphate dihydrate crystal deposition in the cartilage (CPPD).2 Only a few small cohort studies characterize adult HPP in terms of clinical, radiographic and laboratory presentation.

Clinicians should take notice of persistent hypophosphatasemia, consider the diagnosis of HPP and be cautious when considering potent antiremodeling therapy in these adults since the underlying disorder is a defect in mineralization (osteomalacia), not osteoporosis.

Treating HPP

Asfotase alfa has revolutionized the treatment of HPP. Asfotase alfa (Strensiq®), a mineral-targeted recombinant TNSALP, was approved by regulatory agencies in many countries in 2015 for pediatric-onset HPP. Adult treatment is off-label, but since the disease is the result of a genetic variant present at birth, all cases are in essence pediatric, even though those with mild disease may first present for evaluation much later in life. Most of these patients will have had unrecognized disease manifestations in their youth, such as premature loss of primary teeth before the age of five. The tooth loss is characterized by loss of the entire tooth with root intact and is a result of insufficient mineral in the cementum that covers the tooth and anchors the root to the periodontal ligament.

Prior to the availability of asfotase alfa, teriparatide had been used in several case reports with mixed success. Unlike using an antiresorptive agent, an anabolic agent like teriparatide is not likely to be harmful. Since the data on treatment with asfotase alfa is in children, the treatment of adults with HPP is less formulated. Shapiro and Lewiecki suggest treatment of adults be considered one or more of the following is present and determined to be clinically significant and attributable to HPP:

1. Musculoskeletal pain requiring prescription pain medications, especially chronic opioids.
2. Disabling polyarthropathy or chondrocalcinosis.
3. Major low-trauma fracture (e.g., spine, hip, humerus, pelvis) attributable to HPP.
4. Delayed or incomplete fracture healing or fracture nonunion.
5. Repeated episodes of orthopedic surgery for complications of HPP, especially for nonunion and delayed union fractures.
6. Disabling functional impairment (e.g., mobility, gait, activities of daily living) assessed by validated measures.
7. Low bone mineral density by DXA: T-score -2.5 in postmenopausal women and men age 50 years and older, or Z-score -2.0 in younger adult women and men in patients with fractures.
8. Radiological evidence of nephrocalcinosis.

Over the last year we have diagnosed five new cases of HPP. Since our clinic is a referral center, our population would be enriched in a rare metabolic bone disease, but we suspect that one or more cases may be present in many rheumatologic practices, especially practices that evaluate and treat osteoporosis patients.

Dr. Abelson is Chair of the Department of Rheumatic and Immunologic Diseases. Dr. Deal is Director of the Center for Osteoporosis and Metabolic Bone Disease.